Noémie Demaré
email: noemie.demare@aphp.fr

Chantal Julia

Alice Bellicha

Mourad Benallaoua

Amal Ait Omar

Nathalie Arnault

Robert Benamouzig²

Mélanie Deschasaux-Tanguy

Dietary behaviours of individuals with Lynch syndrome at high risk of colorectal cancer: results from the AAS-Lynch study

Keywords: Lynch syndrome, Nutrition, Dietary pattern, Eating habits, Colorectal cancer Lynch syndrome, Nutrition, Dietary pattern, Eating habits, Dietary recommendation, Cancer prevention, Colorectal cancer, Hereditary Cancer, Risk reduction, Nutritional prevention

Background & Aims: Individuals with Lynch syndrome (LS) have a high lifetime risk of developing colorectal cancer (CRC) due to genetic alterations. Nutrition is one of the main modifiable risk factors for sporadic CRC, however this has not been established in LS patients. The present study aimed to give a detailed overview of dietary intakes in individuals with LS, and associated individual characteristics.

Methods: Dietary behaviours of individuals with LS from the AAS-Lynch clinical trial (2017)(2018)(2019)(2020)(2021)(2022) were obtained using a food frequency questionnaire. Dietary intakes, food group consumption and overall diet quality (dietary patterns, adherence to the Mediterranean diet) were described according to sociodemographic, anthropometric and clinical characteristics, and compared to participants without LS from the NutriNet-Santé study (matched on sex, age, BMI and region).

Results: 280 individuals with LS were included in this analysis and matched with 547 controls.

Compared to controls, LS patients consumed less fibre, legumes, fruit and vegetables and more red and processed meat (all p<0.01). They also had a lower Mediterranean diet score (p=0.002). Among LS patients, men, younger patients, or those with disadvantaged situation had a diet of poorer nutritional quality with lower adherence to a "Healthy" diet (all p≤0.01). LS Patients with prevalent CRC had a higher consumption of dairy products than recommended, while those with prevalent adenoma consumed more vegetables, and less sugar and sweets (all p≤0.01).

Conclusions:

Although patients with LS were aware of their high lifetime risk of developing cancer, their diets were not optimal and included nutritional risk factors associated to CRC.

The study is registered with # NCT04791644 at ClinicalTrials.gov.

Introduction

Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with an increased lifetime risk of developing various digestive and extra-digestive cancers. LS results from germline mutation or deletion in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) and is the most common hereditary colorectal cancer (CRC) syndrome, affecting 1 in 279 individuals in Western countries. [START_REF] Win | Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer[END_REF] Several studies have estimated that individuals with LS have 11 to 79 % cumulative risk to develop a CRC by age 70, depending on the type of gene alteration and sex. [START_REF] Bonadona | Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome[END_REF][START_REF] Barrow | Cancer risk in Lynch Syndrome[END_REF][START_REF] Kempers | High colorectal and low endometrial cancer risk in epcam deletion-positive lynch syndrome: a cohort study[END_REF][START_REF] Ten Broeke | Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk[END_REF] In comparison, the risk of developing CRC for the general population aged 50-74 years has been estimated at 3.5 %. [START_REF] Has-Santé | Référentiel de pratiques pour la prévention et le dépistage du cancer colorectal (Practice guidelines for colorectal cancer prevention and screening[END_REF] Nutrition is one of the main modifiable drivers of colorectal carcinogenesis with 22.4 % [START_REF]Cancers attribuables au mode de vie et à l'environnement en France métropolitaine (Cancers attributable to lifestyle and the environment in metropolitan France)[END_REF] of CRC cases attributable to diet. According to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 2018 report, strong convincing evidence showed that body fatness and high consumption of alcohol and processed meat increases the risk of CRC while physical activity decreases CRC risk. In turn, there is probable evidence that adopting "Healthy" dietary habits and in particular increasing the intake of wholegrains, food containing dietary fibres, dairy products and calcium, while limiting red meat intake significantly lower this risk. [START_REF]Food, nutrition, physical activity, and the prevention of cancer: a global perspective[END_REF] In line with this evidence, several studies observed a lower risk of CRC associated with a higher overall diet quality assessed through adherence to the Mediterranean diet [START_REF] Schwingshackl | Adherence to Mediterranean Diet and Risk of Cancer: An Updated Systematic Review and Meta-Analysis[END_REF], a "Healthy" dietary pattern [START_REF] Garcia-Larsen | Dietary patterns derived from principal component analysis (PCA) and risk of colorectal cancer: a systematic review and meta-analysis[END_REF] or to nutritional recommendations (e.g., the French Nutrition and Health Program, PNNS) [START_REF] Chaltiel | Prospective association between adherence to the 2017 French dietary guidelines and risk of death, CVD and cancer in the NutriNet-Santé cohort[END_REF]. Among individuals with LS, smoking [START_REF] Watson | Tobacco Use and Increased Colorectal Cancer Risk in Patients With Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome)[END_REF][START_REF] Van Duijnhoven | Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?[END_REF][START_REF] Pande | Smoking and colorectal cancer in Lynch syndrome: results from the Colon Cancer Family Registry and the University of Texas M.D. Anderson Cancer Center[END_REF], alcohol [START_REF] Dashti | Alcohol Consumption and the Risk of Colorectal Cancer for Mismatch Repair Gene Mutation Carriers[END_REF][START_REF] Miguchi | Alcohol consumption and early-onset risk of colorectal cancer in Japanese patients with Lynch syndrome: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum[END_REF] body mass index (BMI) [START_REF] Van Duijnhoven | Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?[END_REF][START_REF] Win | Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes[END_REF] or physical activity [START_REF] Dashti | Physical activity and the risk of colorectal cancer in Lynch syndrome[END_REF][START_REF] Kamiza | Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome[END_REF], i.e. modifiable factors influencing CRC risk in the general population, appear to be associated with CRC risk. Regarding diet, results on the impact of dietary habits and dietary pattern on CRC carcinogenesis in LS are heterogeneous. [START_REF] Botma | Dietary patterns and colorectal adenomas in Lynch syndrome[END_REF][START_REF] Voskuil | Meat consumption and meat preparation in relation to colorectal adenomas among sporadic and HNPCC family patients in The Netherlands[END_REF][START_REF] Brouwer | Inflammatory potential of the diet and colorectal tumor risk in persons with Lynch syndrome[END_REF][START_REF] Chau | Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome[END_REF] However, there is considerable phenotypic variability in carriers of the same MMR mutation, as well as in disease progression and prognosis within a family with the same mutation, suggesting the influence of environmental factors, and potentially diet. [START_REF] Talseth-Palmer | Genetic modifiers of cancer risk in Lynch syndrome: a review[END_REF] Changes in diet and lifestyle have been identified following a cancer diagnosis. [START_REF] Fassier | Variations of physical activity and sedentary behavior between before and after cancer diagnosis: Results from the prospective population-based NutriNet-Santé cohort[END_REF][START_REF] Fassier | Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population-based NutriNet-Santé cohort[END_REF][START_REF] Fassier | Sociodemographic and economic factors are associated with weight gain between before and after cancer diagnosis: results from the prospective population-based NutriNet-Santé cohort[END_REF] Because of their very high risk of developing CRC and the presence of a family history of cancer, patient with LS may engage in more favourable dietary behaviours but this has not been established yet. [START_REF] Brouwer | Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study[END_REF] A study by Burton and al. suggested rather the opposite, with 50% of individuals with LS that did not report worrying about their diet. [START_REF] Visser | Determinants of adherence to recommendations for cancer prevention among Lynch Syndrome mutation carriers: A qualitative exploration[END_REF] In order to improve the nutritional management of individuals with LS, it is essential to assess their dietary behaviours and to identify groups exposed to nutritional risk factors for CRC.

To our knowledge, no study in France has reported a detailed overview of the dietary habits of people with LS, including the overall quality of their diet and an assessment of their adherence to nutritional recommendations. The objective of our study was therefore to assess the dietary intake of people with LS and to analyse the characteristics of those adopting dietary behaviours known to be associated with a higher or lower risk of CRC in the general population.

Materials and Methods

Study population

Individuals with LS evaluated in this study were volunteers included in the AAS-Lynch study "Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients with Lynch Syndrome" which is a prospective, double-blind, randomized, controlled, multicentre clinical trial designed to assess the effect of daily low doses of aspirin (300 or 100 mg) during 4 years on the occurrence and/or recurrence of colorectal neoplasia in patients with LS [START_REF] Brouwer | Inflammatory potential of the diet and colorectal tumor risk in persons with Lynch syndrome[END_REF]. Trial recruitment started in 2017 and ended in June 2022. Individuals with LS aged 18 to 75 years with a characterized alteration of MMR genes or with a family history of LS according to modified Amsterdam criteria [START_REF] Vasen | New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC[END_REF] and having undergone a colonoscopy within 180 days before inclusion were eligible. Exclusion criteria included total colectomy, adenomatous polyposis associated with known alteration of APC or MYH genes or patients with a diagnosis of cancer or receiving cancer treatment at the time of inclusion. In this study, we used dietary data collected as part of "AAS-Lynch Microbiote", an ancillary study to the AAS-Lynch trial. The AAS-Lynch Microbiote study was approved by the ethics committee of the investigating centre, Avicenne hospital (CLEA-2020-159). The study is registered with # NCT04791644 at ClinicalTrials.gov.

Data collection at inclusion

At inclusion, the patient's personal history (including genetic test results, characteristics of LS, previous colonoscopy results) and family history of cancer were collected from medical records. Colonoscopy was performed within 180 days before inclusion to assess and resect if needed any pre-existing lesions.

Patients also completed self-administered questionnaires related to dietary intakes (see below) and socio-demographic and lifestyle characteristics (smoking status, alcohol consumption), including the EPICES (Evaluation of precariousness and health inequalities in health examination centres) questionnaire to detect and quantify precariousness based on socio-economic, behaviour and health indicators. [START_REF] Sass | Le score Epices : un score individuel de précarité. Construction du score et mesure des relations avec des données de santé, dans une population de 197 389 personnes (The Epices score: an individual precariousness score. Construction of the score and measurement of the relationship with in a population of 197,389 people[END_REF] Anthropometric data (height and weight) were measured by trained staff under standardized conditions.

Dietary assessment

Dietary intakes were assessed at inclusion using the semi-quantitative food frequency questionnaire (FFQ) SU.VI. MAX 2.(32) This validated questionnaire, adapted to French eating habits, assesses usual dietary intakes over the past year. Patients documented their frequency of consumption for each of the 240 food and beverage items. For food categories which are usually not eaten in a predetermined serving size (cheese, pâté, fish, meat, butter used on bread, potatoes, cereal products, vegetables, nuts), they were asked to indicate their usual portion size using 3 photographs and 7 intermediate portion sizes.

Completed questionnaires were reviewed by a dietician and completed in case of invalid dietary data (missing information and misfiling) by contacting the patients (details are available in Supplementary Methods). Average daily energy, alcohol, macro-and micronutrient intakes were estimated from the SU.VI.MAX food composition table by multiplying consumption frequency by serving size for each food and beverage. [START_REF] Hercberg | MAX : table de composition des aliments[END_REF] Comparison with non-LS adults from the NutriNet-Santé study

The eating habits of individuals with LS were compared to eating habits of matched non-LS controls from the NutriNet-Santé cohort.(34) NutriNet-Santé is an observational web-based study launched in France in May 2009 with more than 173 000 registered volunteers with the aim to investigate the relationships between nutrition and health. At inclusion and then annually, participants complete questionnaires on their diet, physical activity, health status (reported health events are validated based on medical records), anthropometric and socio-demographic data. During follow-up, participants are regularly asked to answer additional questionnaires. In 2018, participants completed a FFQ including 264 food and beverage items. [START_REF] Baudry | Contribution of Organic Food to the Diet in a Large Sample of French Adults (the NutriNet-Santé Cohort Study)[END_REF] This validated FFQ was based on the FFQ that has been used in the AAS-Lynch study, with the vast majority of items being identical between the two FFQs. NutriNet-Santé was approved by the Institutional Review Board of the French Institute for Health and Medical Research and by the National Commission on Informatic and Freedom. The cohort is registered with # NCT03335644 at ClinicalTrials.gov.

For each patient included in the AAS-Lynch study, two participants from the NutriNet-Santé study with complete dietary data from the FFQ and without LS or without any family or personal history of cancer, personal history of colonic polyp or oncologic follow up were selected as controls. NutriNet-Santé participants were matched to individuals with LS based on sex, geographical region of residence, age (+/-2 years), BMI (+/-2 kg/m²) and the year of completion of the FFQ (+/-2 years). Overall 39 out of 547 controls were selected with less stringent matching criteria. (Details are available in Supplementary Methods).

Statistical analyses

The eating habits of individuals with LS were described as food group consumption, energy, alcohol, macro-and micronutrient intakes, a posteriori dietary patterns and as adherence to the Mediterranean diet [START_REF] Sofi | Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score[END_REF]. Macro and micronutrient intakes were compared to the European Food Safety Authority's (EFSA) sex and age-specific dietary reference values.(37) (Supplementary Methods). As regards food group consumption, adherence to the most recent French dietary guidelines (PNNS 4, 2017 [START_REF]National Nutrition and Health Programme 2019-2023[END_REF]) (yes/no), which encompass cancer nutrition recommendations issued by the WCRF/AICR (8) adapted to French nutritional specificities [START_REF]Food, nutrition, physical activity, and the prevention of cancer: a global perspective[END_REF], was assessed for 6 'promotion' recommendations related to fruits and vegetables, nuts, legumes, whole grain products, milk and dairy products, fish and seafood and 7 'moderation' recommendations related to alcohol, red meat, processed meat, added fat, sugary foods, sweet-tasting beverages, salt (Supplementary Methods). [START_REF]National Nutrition and Health Programme 2019-2023[END_REF][START_REF] Chaltiel | Programme National Nutrition Santéguidelines score 2 (PNNS-GS2): development and validation of a diet quality score reflecting the 2017 French dietary guidelines[END_REF] , Adherence to the Mediterranean diet was assessed using the MEDI-LITE score [START_REF] Sofi | Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score[END_REF], which attributes points to low, moderate and high consumption of 9 food components that are typical or not typical of the Mediterranean diet (Supplementary Methods). A posteriori dietary patterns were derived from a principal component analysis (PCA) on the daily consumption of food and beverages categorized into 20 main food groups.

Two factors were retained based on the observation of the eigenvalues (measure of the amount of variance explained by each principal axis), the scree plot and interpretability. Orthogonal varimax rotation was used to maximise the independence of these 2 factors. Food groups with a loading coefficient ≥ |0.20| were considered as characterizing the factor and led to identify a "Healthy" pattern and a "Western" pattern (Supplementary Methods).

Comparison of food consumption, nutrient intakes and adhesion to dietary guidelines between individuals with LS and NutriNet-Santé participants was performed using Student t-tests, Wilcoxon test and Pearson's chi-squared test, as appropriate. Among patients with LS, differences in eating habits according to sociodemographic, anthropometric and clinical characteristics were assessed using analysis of covariance (ANCOVA, for continuous dependent variables), logistic regression (for dichotomous dependent variables) or multinomial logistic regression (for dependent variables with >2 categories) models including the following covariates: age (20-40, 40-54 and 55-73 years old), sex, smoking status (never smokers, former smokers, current smokers), energy intake (kcal/d, continuous), body mass index (<18.5, 18.5-24,9, 25.0-29.9 and >29.9 kg.m -2 ), precarity (yes/no), personal history of cancer remission (no, yes: CRC, yes: extra-colic cancer) or colorectal adenoma (yes/no). No significant associations were found with the presence of a partial colectomy, severe anxiety, high blood pressure, a family history of cancer or the inclusion centre. Other comorbidities such as diabetes, metabolic syndrome, hyperthyroidism, peptic ulcer disease or hyperlipidemia were present in a very small number of patients and were not associated with the dietary variables. For all covariates, ≤ 5 % of their values were missing and were imputed to the mean and mode values for continuous and categorical variables respectively.

All tests were two-sided with p < 0.05 was considered statistically significant. Statistical analyses were performed using SAS software (version 9.4; SAS Institute Inc.).

Results

Between November 2017 and May 2022, 316 individuals with LS completed the FFQ. Patients were excluded because of missing data and misfiling (n=34) or missing clinical data (n=2). A total of 280 patients were thus included in this analysis, with a mean age (SD) of 48.0 (11.6) years (range: 20-73 years), 51.4 % of women and a mean (SD) BMI of 25.4 (4.6) kg/m². Active smoking was found in 14.6 % of individuals and 13.9 % were in a disadvantaged situation. More than half of patients had a history of colorectal adenoma (52.1 %) and 39.6 % had a history of cancer (Table1). In all, 276 patients with LS were matched with 547 participants from the NutriNet-Santé study (details are available in Supplementary Table 1). Compared to NutriNet-Santé participants, patients with LS reported lower adherence to dietary recommendations, including lower intakes of fruit (-22 %), vegetables (-22 %) and legumes (-41 %) and higher intakes of red meat (+30 %), processed meat (+41 %), dairy products (+5 %), cake and biscuits (+60 %) and sugar and confectionery (+43 %). These differences in food group consumption were reflected in a lower Mediterranean diet adherence score (MEDI-LITE score) in individuals with LS (9.3 vs 9.9, p=0.002). Looking at macro and micronutrient intakes, patients with LS consumed lower amounts of dietary fibres (-15 %), α-Linolenic acid (ALA) (-50 %), iron (-24%), , vitamin E (-21 %), vitamin C (-15 %), vitamin B9 (-18 %) and higher intake of sodium (+24 %). Consistently, adherence to reference values for these nutrients was lower. No differences were found regarding consumption of nuts, fish, fried products and alcoholic drinks or the intakes of energy, alcohol, calcium.. The results of the paired analyses were identical (data not shown). Vitamin B6 (mg/day) 1.9 1.9 0.47 1.8 1.9 1.9 0.42 1.8 1.9 1.9 0.52 1.9 1.9 1.8 0.30 1.9 1.9 0.43 1.9 1.9 1.9 0.93 1.9 Focusing on patients with LS, we found in men higher intakes in energy, alcohol, cereal products (bread, pasta, rice, potato) and fried products and in women higher intakes of fibre, lipids (MUFA, PULA, ALA and LA) vitamin C, E and their food sources, namely fruit and vegetables and nuts. (Table 3 and Table 4) Hence, women were also more likely to meet the recommendations for fruit, vegetables, nuts, alcohol, ALA, vitamin C and E (Supplementary Table S2 andS3). If we look at the overall quality of the diet, men were more likely to consume a "Western" diet.(Table 4) Older age was associated with higher intakes in vegetables, fibres and lower intakes in processed meat and fried products. (Table 3 and Table 4) Their diet scored higher on the MEDI-LITE scale and showed a lower adherence to the "Western" dietary pattern. (Table 4) Former smokers and active smokers had higher intake of coffee and were less likely to follow the alcoholic beverage recommendation. (Table 4 and Supplementary Table S2) Patients with LS in a disadvantaged situation had higher intakes of protein of animal origin, processed meat and fried products, lower intakes of vegetable protein and fibre (Table 3 and4) and adhered less to the reference values for the ratio olive oil/ALA-rich oil and ALA (Supplementary Table S2 andS3) and to a "Healthy" dietary pattern. (Table 4) Patients with a history of extra-colonic cancer consumed more lipids and SFAs, those with a history of CRC consumed more cholesterol (Table 3) and had a higher adherence to the recommendation for dairy products (Supplementary Table S3). Patients with a history of colorectal adenomas had higher intakes of vegetables and lower intakes of sugar and confectionery.

(Table 4) We did not find any significant difference in food consumption, compliance with recommendations or overall diet quality according to BMI.

Discussion

In this study, we provided an extensive overview of dietary behaviours, including food group consumption, nutrient intakes and diet quality, of patients with LS from the AAS-Lynch clinical trial.

Our analysis of the dietary habits of these LS patients compared to a non-LS population from the NutriNet-Santé study showed a less favourable nutritional profile, which is associated in the general population with a higher risk of CRC. Furthermore, in our LS population, we distinguished specific groups with potentially risky behaviours with regard to dietary risk factors for CRC.

To the best of our knowledge, this is the first French study to extensively characterize the dietary behaviour of patients with LS, including a comparison with a matched sample from the general non-LS population. The diet of individuals with LS was overall of poorer nutritional quality. Indeed, they consumed less fruit, vegetables, legumes, nuts, and oily fish but more red and processed meat as well as sweet beverage, cake and biscuit, sugar and confectionery. Hence, they also deviated from the characteristics of the Mediterranean diet. At the nutrient level, this was reflected by lower intakes of and adherence to the reference values for dietary fibre, ALA, vitamins including antioxidant vitamins [START_REF] Carlsen | The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide[END_REF] (vitamin C, E, B2, B6 and B9) and minerals (iron, potassium, magnesium, iodine) and a higher sodium intake. Yet, according to the WCRF/AICR, foods containing dietary fibre are likely to be protective against CRC, while the consumption of red and processed meat constitute an established risk factor for CRC.( 8) Hence, in this study individuals with LS seemed to adopt more at-risk eating habits as regards CRC, but also more generally to have a more unbalanced diet, with potential consequences for their overall health.( 41 Our study compared LS patients to participants in the NutriNet-Santé cohort as non-LS controls.

However, it should be noted that participants in the NutriNet-Santé study were volunteers, with a higher level of education and healthier eating behaviours compared to the general population. [START_REF] Andreeva | Comparison of the sociodemographic characteristics of the large NutriNet-Santé e-cohort with French Census data: the issue of volunteer bias revisited[END_REF][START_REF]Comparison of Dietary Intakes Between a Large Online Cohort Study (Etude NutriNet-Santé) and a Nationally Representative Cross-Sectional Study (Etude Nationale Nutrition Santé) in France: Addressing the Issue of Generalizability in E-Epidemiology[END_REF] Hence, this could increase the differences in consumption observed between LS and NutriNet-Santé individuals.

Indeed, when comparing our results with the results of the French nationally representative INCA3 survey (n=2121) and Esteban study (n=1627), we observed that patients with LS were more in line with the recommendations for fruit and vegetables and legumes and consumed slightly more dietary fibres. [START_REF] Torres | Adequacy of the new dietary recommendations of adults aged 18-54 living in France[END_REF][START_REF]Third national individual food consumption study (INCA3 study).Updating of the database on food consumption and the estimation of nutritional intakes of individuals living in France[END_REF] However, similar to the comparison with NutriNet-Santé participants, patients with LS were more likely to follow the recommendations for the consumption of dairy products and less likely for the recommendations regarding red or processed meats compared to the general population. Yet, these comparisons are not straightforward due to differences in the tools used to assess dietary intakes (FFQ in our study vs. 24-hour recalls in INCA 3 and Esteban study, which tend to over-and underestimate dietary intakes, respectively [START_REF] Landais | Les mesures de la consommation alimentaire individuelle : des méthodes en fonction des objectifs visés[END_REF]), but also differences in the characteristics of the populations (e.g., age, sex, weight status). In contrast, AAS-Lynch and NutriNet-Santé studies used very similar tools to assess dietary intakes and participants were matched to ensure better comparability of the results.

Our study also allowed to identify groups of LS patients with more risky eating behaviours. Indeed, our results showed that men with LS had overall dietary habits more at risk for CRC compared to women.

They consumed almost twice as many alcohol and tended to consume a more "Western-like" dietary pattern whose constituents include CRC risk factors (alcohol, red meat and processed meat). Conversely, they were less likely to adhere to a "Healthy" diet that included CRC protective factors (fibre-rich foods and dairy products). These results were similar to those observed in INCA3 survey for the general French population where a higher consumption of alcoholic beverages, meat and processed meat was observed in men while women consumed more yoghurt, cottage cheese, and had higher intakes of fibre, calcium, vitamin C and B9.(47) Younger patients with LS tended to have a less balanced diet, with the consumption of food groups positively associated with CRC risk. This trend was also seen in the general population from INCA3 and Esteban studies where the level of consumption and adherence to the fruit and vegetable recommendation was higher in older subjects.(46) However, unlike the general population where adults aged 65-79 years are more likely to consume alcoholic beverages compared to those aged 18-44 years, we did not observe a significant difference in individuals with LS in terms of consumption or compliance with alcohol recommendations according to age. [START_REF]Third national individual food consumption study (INCA3 study).Updating of the database on food consumption and the estimation of nutritional intakes of individuals living in France[END_REF] In addition, individuals with LS in disadvantaged situation were less likely to adhere to a "Healthy" dietary pattern, and their intake in vegetables, fibre and magnesium was lower. Conversely, their diet contained higher levels of protein of animal origin, processed meat and fried products. Knowing that a high level of precariousness was present among the most disadvantaged social categories and was associated with a lower level of education and instability in employment, our results are consistent with those observed in the French and European populations. [START_REF]Third national individual food consumption study (INCA3 study).Updating of the database on food consumption and the estimation of nutritional intakes of individuals living in France[END_REF][START_REF] Hassen | Socioeconomic Indicators Are Independently Associated with Nutrient Intake in French Adults: A DEDIPAC Study[END_REF][START_REF] Giskes | A systematic review of studies on socioeconomic inequalities in dietary intakes associated with weight gain and overweight/obesity conducted among European adults[END_REF] Indeed, a low level of education was associated with a lower intake of fibre, magnesium, vitamin C (49) as well as a lower consumption of fruit, vegetables or dairy products(47,50) and higher protein intake and meat consumption [START_REF]Third national individual food consumption study (INCA3 study).Updating of the database on food consumption and the estimation of nutritional intakes of individuals living in France[END_REF][START_REF] Hassen | Socioeconomic Indicators Are Independently Associated with Nutrient Intake in French Adults: A DEDIPAC Study[END_REF]. People with a low income level also had a lower intake of magnesium, potassium and vitamin C. [START_REF] Hassen | Socioeconomic Indicators Are Independently Associated with Nutrient Intake in French Adults: A DEDIPAC Study[END_REF] As observed in the general population, smokers and ex-smokers in LS patients accumulated risk factors for CRC by being less likely to follow the recommendations on alcohol. This correlation between smoking and alcohol consumption has been established in the literature [START_REF] Friedman | Alcohol drinking and cigarette smoking: an exploration of the association in middle-aged men and women[END_REF] and both factors are associated with the risk of CRC in the general population but also in patients with LS. [START_REF] Pande | Smoking and colorectal cancer in Lynch syndrome: results from the Colon Cancer Family Registry and the University of Texas M.D. Anderson Cancer Center[END_REF][START_REF] Dashti | Alcohol Consumption and the Risk of Colorectal Cancer for Mismatch Repair Gene Mutation Carriers[END_REF][START_REF] Winkels | Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome[END_REF] In turn, patients with LS with a history of colorectal neoplasia (cancer or adenoma) tended to consume a more balanced diet in terms of nutritional factors associated with CRC, with more vegetables and higher calcium intake and dairy product consumption. Similar results were shown in CRC survivors (n=116) where 33 % reported changes in their dietary habits aimed at coping or reducing the risk of CRC. [START_REF] Patterson | Changes in diet, physical activity, and supplement use among adults diagnosed with cancer[END_REF] In the study of Bours et al., 36 % of CRC survivors (n=1458) reported having made "Healthy" dietary changes, among which many were CRC risk factors.(54) Contradictory results were found in patients with LS from a Dutch cohort (n=324) where no significant association was found between the diagnosis of colorectal neoplasia and changes in dietary habits. [START_REF] Brouwer | Is a colorectal neoplasm diagnosis a trigger to change dietary and other lifestyle habits for persons with Lynch syndrome? A prospective cohort study[END_REF] Similarly, in the study by Hoedjes et al. in 211 Dutch patients with LS, no significant association was found between adherence to WCRF recommendations and having a personal history of cancer.( 43) These few differences between patients with and without a history of colorectal neoplasia in our study may be explained by the long average time between the diagnosis of the last cancer and the assessment of dietary habits. In addition, the diagnosis of LS and/or having a first-degree relative with cancer could also lead to a change in dietary behaviour and thus blur the differences in behaviour related to personal cancer history. [START_REF] Lemon | Health behavior change among women with recent familial diagnosis of breast cancer[END_REF] Our data indicate that the dietary intakes of patients with LS were not optimal and could therefore benefit from dedicated measure. When interviewed at a conference on LS, individuals with LS and their relatives reported their educational needs and topics of particular interest.( 56) Seventy-one percent indicated a need for education in the area of nutrition and its impact on the disease, as well as monitoring and prevention options. However, some limitations should be acknowledged. Although this is the largest study in France on the dietary intakes of patients with LS, our sample size was still limited, which may have hampered our ability to detect associations. In addition, as described above, the higher level of education and healthier eating behaviour of participants in the NutriNet-Santé study [START_REF] Andreeva | Comparison of the sociodemographic characteristics of the large NutriNet-Santé e-cohort with French Census data: the issue of volunteer bias revisited[END_REF][START_REF]Comparison of Dietary Intakes Between a Large Online Cohort Study (Etude NutriNet-Santé) and a Nationally Representative Cross-Sectional Study (Etude Nationale Nutrition Santé) in France: Addressing the Issue of Generalizability in E-Epidemiology[END_REF] could increase the differences in consumption observed between LS and NutriNet-Santé individuals. In addition, our FFQ did not assess intakes of wholegrain foods, ultra-processed foods or the absolute value of antioxidant intakes. Still, our analyses included the intake of some antioxidant vitamins, antioxidant-rich food sources as well as adherence to the Mediterranean diet, whose adherence is associated with a higher level of antioxidant intakes. [START_REF] Pitsavos | Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study[END_REF] The level of nutritional education of the participants was not measured through the questionnaire, however the inclusion centre was considered in our analyses and allowed to verify the absence of a "centre" effect (with corresponding care protocols) on dietary consumption. The level of physical activity as well as the socio-economic status (beyond precariousness) were not available at the time of the analysis and thus could not be included in our analyses. Finally, no significant association were found between nutritional intakes and comorbidity. Nutritional intakes could be impacted by other non-cancer comorbidities. In our sample, only a few LS patients had comorbidities such as diabetes, metabolic syndrome, hyperthyroidism, peptic ulcer or hyperlipidemia. Hence these either could not been considered as independent factors in our analyses or were not associated with dietary behaviours.

However, we did include BMI categories in our analyses and found no significant difference.

In conclusion, our study provided extensive data on the dietary behaviour of patients with LS. Our data indicate that, although patients with LS were aware of their high lifetime risk of developing cancer, their diets were not optimal and thus could be improved. Our study also showed that among patients with LS, being a man, younger or in a disadvantaged situation was associated with lower diet quality, which is a well-recognized risk factor for CRC. These results may therefore help improve patient stratification and may have important clinical implications. Further steps will be to measure the association between dietary habits and colorectal carcinogenesis in these patients with LS, which will help to identify potential levers to better define nutrition-based prevention strategies in this high-risk population.

Finally, a gap analysis conducted in patients with LS and their caregivers could be an interesting approach in order to identify the various gaps in current nutritional prevention strategies and thus have a substantial impact on colorectal cancer management and prevention. ( 59 a: Sugar and confectionery: sugar, honey, jam, spread, chocolate, candy, dessert cream and ice cream.

b: "Western" pattern: loading coefficient ≥ |0.20| with red meat, poultry, processed meat, egg, potato, starch without potato, fried products, fats and sauces, cake and biscuits, sugar and confectionery, sweetened and alcohol drinks.

c : "Healthy" patter n: loading coefficient ≥ |0.20| with vegetables, fruits, legumes, egg, fish and seafood, dairy products, breakfast cereals, nuts, fats and sauces and hot drinks.

( 56 )

 56 Oncogenetic consultations at the time of providing LS testing results may provide a good opportunity to discuss with the patients about preventive measures and nutritional risk and protective factors related to CRC. Although no standardised prevention methods are performed during oncogenetic follow-up, several studies showed that it was possible to promote healthier nutritional behaviours during genetic testing consultations.[START_REF] Bannon | Patient-reported disease knowledge and educational needs in Lynch syndrome: findings of an interactive multidisciplinary patient conference[END_REF] In addition, nutritional interventions during consultations seem to be the most promising in encouraging behaviour change.(57) More specifically in LS, the provision of awareness materials around the WCRF cancer prevention guidelines has improved patient knowledge, yet with no difference in their adherence to the recommendations.[START_REF] Vrieling | Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers: Randomized controlled trial[END_REF] This study had several strengths. First, the patients were confirmed carriers of MMR mutations from 37 centres across France reflecting a diversity of profiles. Secondly, dietary intakes of patients with LS were compared to volunteers from the NutriNet-Santé study of similar gender, age, BMI and geographical region of residence and using similar dietary assessment tools. Third, dietary data were obtained from a FFQ representative of French consumption habits and validated in the French population, which made it possible to consider the whole diet through daily consumption of foods, nutrient intakes as well as overall dietary patterns. Fourth, clinical and anthropometric data were obtained from medical records or measured by trained staff and were therefore not subject to recall or reporting bias.

Table 2

 2 displays dietary intakes (food groups and nutrients) and adherence to the recommendations for individuals with LS and NutriNet-Santé participants.

Table 1 :

 1 Description of characteristics of LS patients (AAS-Lynch study, n=280)

	AAS-Lynch (n=280)
	n	%

Table 2 :

 2 Comparison of food group intakes, MEDI-LITE score, nutrients intakes and adherence to reference values between patients with Lynch syndrome (AAS-Lynch study 2017-2022, n=276) and controls (NutriNet-Santé 2009-2022, n=547).

		AAS-Lynch	NutriNet-Santé		AAS-Lynch	NutriNet-Santé
		means (std)	p*	Adherence with reference value / recommendation (%)	p**
	Food group intakes
	Fruit (g/day)	211.3 (1723.0)	270.0 (235.9)	0.0001
					51.8	68.6	<0.0001
	Vegetable(g/day)	266.1 (185.0)	341.7 (215.8)	<0.0001
	Legume (g/day)	14.2 (19.8)	24.1 (39.6)	0.006	37.0	41.5	0.21
	Unsalted nuts (g/day)	6.6 (9.9)	7.5 (13.9)	0.29	19.9	20.3	0.90
	Bread, pasta, rice (g/day)	223.2 (112.1)	204.2 (165.1)	0.04	/	/	/
	Potato (g/day)	25.2 (23.7)	18.3 (18.5)	<0.0001	/	/	/
	Red Meat (g/day)	71.2 (55.6)	54.6 (53.6)	<0.0001	61.2	72.8	<0.001
	Processed Meat (g/day)	43.9 (32.7)	31.0 (27.1)	<0.0001	21.7	44.8	<0.0001
	Fish (g/day)	43.3 (39.5)	50.7 (52.6)	0.38	23.6	16.6	0.02
	Oily fish (g/day)	18.7 (20.8)	27.2 (31.8)	<0.001	42.8	33.5	0.009
	Dairy product (g/day)	309.5 (227.5)	295.8 (313.2)	0.04	26.8	20.5	0.04
	Cake and biscuit (g/day) Sugar and confectionery (g/day) a	57.9 (63.3) 56.5 (54.6)	36.5 (35.3) 39.5 (34)	<0.0001 <0.0001	85.1 b	98.5 b	<0.0001
	Fried product	14.5 (18.0)	13.8 (17.5)	0.11	/	/	/
	Rich in ALA or olive oil	9.8 (9.2)	17.1 (15.2)	<0.0001	73.9	66.3	0.03
	Sweet beverage (g/day)	183.5 (257.6)	124.4 (168.8)	0.001	80.7	82.3	0.44
	Alcohol drink (g/day)	89.1 (106.2)	100.9 (163)	0.81	84.4	84.1	0.90
	Salt	8.2 (3.1)	6.7 (3.3)	<0.0001	21.1	46.6	<0.0001
	MEDI-LITE score	9.3 (2.5)	9.9 (2.8)	0.002
	Nutrient intakes
	Total intake energy (kcal/day)	2181.2 (729.9)	2161.5 (925.6)	0.74	-	-	-
	Proteins (g/day)	96.9 (34.9)	96.4 (46.1)	0.86	7.6	8.8	0.57
	Carbohydrates (g/day)	219.6 (82.2)	203.0 (93.2)	0.009	25.7	15.2	<0.001
	Fibres (g/day)	20.7 (8.3)	24.5 (12.2)	<0.0001	26.1	38.2	<0.001
	Lipids (g/day)	95.9 (38.4)	100.2 (49.8)	0.17	24.6	15.5	0.002
	Saturated Fatty Acids (g/day)	37.8 (17.0)	36.3 (19.8)	0.28	3.3	5.9	0.11
	Linoleic acid (g/day)	11.5 (5.8)	13.9 (9)	<0.0001	32.6	18.7	<0.0001
	α-Linolenic acid (g/day)	1.2 (0.7)	2.4 (2)	<0.0001	25.7	90.0	<0.0001
	Eicosapentaenoic acid (g/day)	0.1 (0.1)	0.2 (0.2)	<0.0001
					61.2	64.9	0.30
	Docosahexaénoïque acid (g/day)	0.3 (0.2)	0.3 (0.3)	0.61
	Alcohol (g/day)	7.5 (9.4)	7.9 (10.9)	0.58	84.3	84.1	0.94
	Sodium (mg/day)	3294.5 (1259.3)	2679.8 (1304.0)	<0.0001	9.1	29.3	<0.0001
	Calcium (mg/day)	1182.0 (512.4)	1173.5 (599.5)	0.83	58.3	59.6	0.73
	Iron (mg/day)	12.3 (4.1)	16.4 (7.2)	<0.0001	54.4	77.2	<0.0001
	Potassium (mg/day)	3241.6 (1120.8)	3906.6 (1535.6)	<0.0001	33.7	57.6	<0.0001
	Magnesium (mg/day)	344.2 (108.3)	519.3 (225.1)	<0.0001	51.5	84.1	<0.0001

-: Adherence to the EFSA reference value was not assessed for energy intake as physical activity levels were not available /: There are no recommendations for these dietary intakes a: Sugar and confectionery: sugar, honey, jam, spread, chocolate, candy, dessert cream and ice cream b: Recommendation for sweet products: sugar, honey, jam, spread, chocolate, candy, dessert cream, ice cream, cake and biscuit c: MEDI-LITE score ranges from 0 to 18 *: p-values derived from a Student t-tests or Wilcoxon test **: p-values derived from a Pearson's chi-squared test

Table 3 :

 3 Nutrients intakes of patients with Lynch syndrome according to individual characteristics, AAS-Lynch study 2017-2022.

		Sex			Age (years)			BMI (kg/m²)		Smoking status	Situation of precariousness		History cancer		History colorectal adenoma
	Nutrients Intakes*	Men Women	p*	[20-40[	[40-55[	[55-73[	p*	<25	[25-30]	>30	p*	Non-smoker	Former smoker	Smoker p*	No	Yes	p*	No	CRC	Extra-cancer colic	p* No	Yes	p*
	Total intake energy (kcal/day)	2436	2139	0.002	2344	2293	2225 0.63 2278 2198 2387 0.43	2189	2358	2316 0.22	2305	2271 0.80 2222 2205	2436 0.16 2309 2266 0.65
	Proteins (g/day)	99.9	99.9	0.99	100.3	100.0	99.3 0.93	97.1 100.7 101.8 0.17	100.2	101.1	98.2 0.68	97.8	101.9 0.17	99.9	97.7	102.0 0.43	99.0 100.7 0.44
	Animal proteins (g/day)	74.7	74.6	0.98	75.2	74.9	73.8 0.90	72.3	76.0	75.6 0.31	75.0	75.9	72.9 0.72	71.0	78.2 0.03	74.2	71.9	77.9 0.26	74.2	75.1 0.69
	Vegetable proteins (g/day)	25.2	25.3	0.96	25.1	25.1	25.4 0.94	24.8	24.7	26.2 0.44	25.2	25.2	25.3 1.00	26.8	23.7 0.01	25.7	25.8	24.1 0.25	24.9	25.6 0.37
	Carbohydrates (g/day)	217.9	209.8	0.16	212.3	212.8	216.4 0.82 214.2 209.9 217.4 0.65	215.3	207.7	218.6 0.33	221.0	206.7 0.07 221.0 216.0	204.5 0.07 216.2 211.5 0.40
	Simple carbohydrates (g/day)	97.4	102.5	0.26	95.7	99.7	104.5 0.33 103.4 102.2	94.4 0.41	103.1	96.0	100.9 0.34	105.1	94.9 0.11 103.5	99.2	97.3 0.48 102.5	97.5 0.27
	Fibres (g/day)	18.2	20.0	0.02	17.5	19.0	20.9 0.01	19.3	18.9	19.1 0.90	19.7	19.6	18.1 0.37	20.6	17.7 0.01	19.5	19.7	18.2 0.42	18.5	19.7 0.14
	Lipids (g/day)	95.0	101.7	0.001	99.2	99.1	96.8 0.55	99.7	99.8	95.6 0.35	98.6	100.1	96.3 0.45	96.0	100.7 0.10	95.4	97.5	102.2 0.02	97.8	98.9 0.61
	SFA (g/day)	38.5	39.7	0.29	39.2	39.5	38.5 0.72	39.9	39.3	38.0 0.47	39.0	39.7	38.6 0.75	37.9	40.2 0.12	37.6	38.4	41.2 0.03	38.4	39.8 0.19
	MUFA (g/day)	36.5	39.9 >0.001	38.8	38.6	37.3 0.36	38.7	38.8	37.2 0.52	38.3	39.2	37.2 0.38	37.6	38.9 0.35	37.2	37.9	39.6 0.13	38.4	38.1 0.72
	PULA (g/day)	13.5	15.5	0.001	14.7	14.4	14.5 0.90	14.4	15.2	13.9 0.33	14.7	14.6	14.2 0.80	14.0	15.1 0.18	14.1	14.6	14.9 0.52	14.5	14.5 0.93
	Linoleic acid (g/day)	11.2	12.9	0.003	12.4	11.9	11.9 0.66	12.0	12.6	11.5 0.37	12.2	12.0	11.9 0.89	11.4	12.7 0.07	11.7	12.0	12.4 0.59	12.0	12.1 0.89
	α-Linolenic acid (g/day)	1.0	1.2 >0.001	1.0	1.0	1.2 0.05	1.1	1.2	1.0 0.24	1.1	1.2	1.0 0.25	1.2	1.0 0.09	1.0	1.1	1.2 0.06	1.1	1.1 0.86
	Eicosapentaenoic acid (g/day)	0.1	0.1	0.74	0.1	0.1	0.2 0.24	0.1	0.1	0.2 0.75	0.1	0.2	0.1 0.50	0.2	0.1 0.14	0.1	0.1	0.1 0.79	0.1	0.1 0.35

  Adjusted means and p-values derived from an ANCOVA model adjusted for sex, age, BMI, smoking status, situation of precariousness, history of cancer and history of colorectal adenomas. pattern: loading coefficient ≥ |0.20| with red meat, poultry, processed meat, egg, potato, starch without potato, fried products, fats and sauces, cake and biscuits, sugar and confectionery, sweetened and alcohol drinks.

	Sugar and
	confectionery	50.4	42.9		0.23 42.6 49.8	47.5	0.64 49.2 53.9 36.9 0.22	48.6	51.4	40.0 0.49 52.4	40.9 0.18	49.8	52.4	37.7	0.23	54.9	38.4	0.01
	(g/day) a															Situation of			History
			Sex				Age (years)		BMI (kg/m²)			Smoking status					History cancer	colorectal
	Fried product															precariousness
		249.8	205.9		0.04 238.3 221.7 223.4 <0.001 217.6 212.1 253.8 0.75	229.0	224.4	230.1 0.07 224.8	230.8 0.01 244.1 232.8	206.6	adenoma 0.14 228.7 226.9	0.05
	(g/day)
																				Extra-
	Food Group Sweetened soft					[20-	[40-	[55-		[25-			Non-	Former
		Men Women 173.7 217.1		p* 0.15 241.5 185.0 159.7	p* 0.11 161.5 208.3 216.3 0.24 <25 >30 p*	193.8	144.9	Smoker 247.4 0.07 212.1 p* No	Yes 178.7 0.43 199.8 188.4 p* No CRC	colic 198.0	p* 0.95 219.7 171.1 No Yes	p* 0.11
	Intakes (g/day)					40[	55[	73[		30]			smoker	smoker
																				cancer
	Alcohol drinks
	Fruit (g/day)	154.3 120.0	208.6 69.4 <0.001 92.5 85.7 105.8 0.01 134.1 186.8 223.4	0.005 192.0 191.6 160.6 0.57 0.41 89.7 92.4 102.0 0.82	193.3 78.1	190.6 108.6	160.3 0.53 198.8 97.5 0.08 102.3	164.0 0.23 184.0 191.5 87.1 0.41 87.3 111.4	168.7 85.5	0.76 174.4 188.4 0.29 90.5 98.9	0.49 0.51
	(g/day)
	Vegetable
	Coffee (ml/day)	211.7 192.9	275.7 166.8		0.003 209.4 232.3 289.2 0.17 166.5 176.2 196.9	0.01 252.4 233.2 245.4 0.69 0.44 193.4 171.4 174.8 0.51	257.4 144.5	256.1 195.9	217.6 0.41 263.0 199.2 0.02 206.4	224.4 0.19 239.7 246.1 153.3 0.05 185.7 190.4	245.2 163.4	0.96 217.7 269.6 0.58 158.8 200.9	0.01 0.03
	(g/day)
	Legume (g/day) Tea (ml/day)	11.1 59.4	15.3 237.4		0.09 13.4 13.4 0.002 75.4 196.7 172.9 12.7	0.97 13.3 14.5 11.7 0.76 0.19 228.4 181.6 35.1 0.06	13.1 170.0	14.5 158.4	12.0 0.77 14.3 116.6 0.80 205.6	12.1 0.53 91.0 0.14 118.3 179.2 12.4 11.6	15.5 147.4	0.55 0.66 189.7 106.9 11.5 14.9	0.18 0.13
	Nuts (g/day) MEDI-LITE score 8.92 4.5	7.4 9.35		0.02 0.16 8.82 8.89 5.5 6.4	6.0 9.69	0.84 0.04 9.29 9.11 9.01 0.75 5.5 6.7 5.6 0.67	6.1 9.02	6.5 9.01	5.2 0.82 9.37 0.70 9.13 7.2	4.6 0.15 9.47 8.81	5.1 0.37	5.5 8.99	7.2 9.28	0.41 0.34	5.8 9.51	6.1 8.76	0.76 0.08
	Bread, pasta, rice Dietary Patterns
	(g/day) "Western" diet b 0.25 20.4	16.3 <0.001 24.4 17.4 0.07 0.02 0.37 0.10 -0.001 <0.001 0.05 0.15 0.27 0.10 13.2 0.46 18.2 17.3 19.6 0.06	16.0 0.08	16.5 0.15	22.6 0.92 14.5 0.24 0.30 0.06	22.2 0.71 0.25 0.06	20.7 0.16	15.9 0.22	18.5 0.10	0.03 0.57	16.4 0.20	1.9 0.35 20.3 0.87 0.12 0.24
	Vitamin B9(µg/day)	317	361	0.001	315	337	366 0.02	341	345	332 0.83	349	347	322 0.36	349	330 0.30	337	342	340 0.95	351 0.07
	Vitamin B12(µg/day) Potato (g/day) 29.2 "Healthy" diet c -0.36	22.1 -0.01	7	7 0.01 22.7 24.3 0.94 0.001 -0.39 -0.21	6 29.9 0.06	7 0.09 23.6 22.2 31.1 0.10 7 0.19 7 7 0.01 -0.12 -0.20 -0.23 0.71	7 0.79 23.8 -0.15	7 27.1 -0.11	7 26.0 0.50 28.5 7 0.49 -0.29 0.57 0.00	7 22.8 0.13 7 0.59 24.9 -0.36 0.02 -0.20 -0.11 7 27.1	7 -0.24 24.9	7 0.80 0.80 0.74 -0.24 -0.13 7 25.3 26.0	7 0.96 0.78 0.33
	Red meat
		80.8	71.9		0.16 76.7 78.8	73.4	0.76 71.7 78.9 78.3 0.52	78.2	76.3	74.4 0.91 69.3	83.3 0.11	76.7	74.6	77.6	0.95	75.5	77.1	0.80
	Abbreviation: BMI: Body Mass Index. (g/day) Abbreviation: BMI: Body Mass Index.
	Processed Meat
		49.5	47.9		0.66 50.2 54.0	41.9	0.02 46.7 44.6 54.8 0.22	49.0	55.0	42.2 0.07 41.3	56.1 0.01	48.7	46.2	51.2	0.69	48.4	49.0	0.87
	(g/day)
	Fish (g/day)	37.5	42.3		0.48 32.5 37.6	49.6	0.13 38.7 36.5 44.4 0.76	39.2	44.9	35.6 0.61 46.0	33.8 0.20	44.0	40.0	35.8	0.61	41.2	38.6	0.71
	Dairy product
	(g/day) c : "Healthy" patter	285.1	306.1		0.43 275.6 294.0 317.4	0.47 306.8 294.0 286.1 0.83	318.8	302.2	265.9 0.38 282.0	309.3 0.46 322.1 247.4	317.5	0.07 288.8 302.5	0.60
	Cake and biscuit n: loading coefficient ≥ |0.20| with vegetables, fruits, legumes, egg, fish and seafood, dairy products, breakfast cereals, nuts, fats and sauces and hot drinks.
		56.6	56.4		0.98 59.7 59.5	50.4	0.48 59.3 55.8 54.5 0.85	52.2	45.6	71.7 0.06 64.4	48.6 0.11	53.7	62.1	53.7	0.62	59.9	53.1	0.33
	(g/day)

*:

*: Adjusted means and p-values derived from an ANCOVA model adjusted for sex, age, BMI, smoking status, situation of precariousness, history of cancer and history of colorectal adenomas. a: Sugar and confectionery: sugar, honey, jam, spread, chocolate, candy, dessert cream and ice cream. b: "Western"

table 2 :

 2 ) B) Recommendations of PNNS 4 and corresponding indicators used to assess adherence. Adherence of PNNS 4 recommendation of patients with Lynch syndrome according to individual characteristics, AAS-Lynch study 2017-2022.

	Dietary intake	Recommendations	Indicators used
	Fruits and vegetables	At least 5 fruits and vegetables a day	≥ 400 g / day
	Unsalted nuts	A small handful a day	≥ 10 g / day	a
	Legumes	At least twice a week	≥ 2 / week
	Dairy products	2 dairy products per day	2 / day
	Meat and poultry	Favour poultry and limit other meats (pork, beef, veal, mutton, lamb, offal) to 500 g per week	< 500 g red meat / week
	Fish and sea food		1.5 -2.5 / week
		2 times a week, including one oily fish
			0.5 -1.5 / week
	Processed meat	Limit processed meats to 150 g per week	< 150 g / week
	Added fats (AF)	AF -oil, butter and margarine -can be consumed daily in small amounts.	< 16 % of EIWA
			AF vegetal origin > AF animal origin
		Choose rapeseed, walnut and olive oil	AF rich in ALA or olive oil / AF of vegetable origin > 50 %
	Sweet Products		Simple carbohydrates from sweet products
		Limit the consumption of sweet products	< 12.5 % de l'EIWA	b
	Sweet Drinks	Limit the consumption of sweet drinks	consumption of sweet drinks < 250 mL / day
	Salt	Reducing salt consumption	6 g / day
	Alcohol	Maximum 2 drinks per day and not every day	< 100 g / week
	Abbreviation: PNNS: Programme National Nutrition Santé.
	Nutrient intake	Male	Female
	Dietary fibre		25 g/day
	Total carbohydrates		45-60 % of energy
	Protein		0.83 g/kg
	Total fat		20-35 % of energy
	Alpha-linolenic acid (ALA)		0.5 % of energy
	Eicosapentaenoic acid, Docosahexaenoic acid (EPA, DHA)	250 mg/day DHA +EPA
	Linoleic acid (LA)		4 % of energy
	Calcium	1000 mg/day	950 mg/day
	Iodine		150 μg/day
	Iron	11 mg/day	16 mg/day
	Magnesium	350 mg/day	300 mg/day
	Phosphorus		550 mg/day
	Potassium		3500 mg/day
	Sodium		2 g/day
	Thiamin (Vitamin B1)		0.1 mg/MJ

a) Use of the same indicator as in the Esteban study: At least one reported consumption during the three 24-hour recall days. b) Abbreviation: EIWA: Energy intake without alcohol. C) Dietary reference values from ESFA used to assess adherence.

Sex Age (years) BMI (kg/m²) Smoking status Situation of precariousnes s History cancer History colorectal adenoma Women vs

  : Adjusted means and p-values derived from an ANCOVA model adjusted for sex, age, BMI, smoking status, situation of precariousness, history of cancer and history of colorectal adenomas.

	Nuts (g/day) Tea (ml/day)		4.5 59.4	7.4 237.4	0.02 0.002 75.4 196.7 172.9 5.5 6.4 6.0	0.84 0.19 228.4 181.6 35.1 0.06 5.5 6.7 5.6 0.67	6.1 170.0	6.5 158.4	5.2 0.82 116.6 0.80 205.6 7.2		4.6 0.15 91.0 0.14 118.3 179.2 5.1 5.5	7.2 147.4	0.41 0.66 189.7 106.9 5.8 6.1	0.76 0.13
	Bread, pasta, rice MEDI-LITE score	8.92	9.35	0.16 8.82 8.89	9.69	0.04 9.29 9.11 9.01 0.75	9.02	9.01	9.37 0.70 9.13		9.47 8.81	0.37	8.99	9.28	0.34	9.51	8.76	0.08
			20.4	16.3 <0.001 24.4 17.4	13.2	0.46 18.2 17.3 19.6 0.06	16.0	16.5	22.6 0.92 14.5		22.2 0.71	20.7	15.9	18.5	0.03	16.4	20.3	0.87
	(g/day) Dietary Patterns
	Potato (g/day) "Western" diet b 0.25 29.2	22.1 0.07	0.01 22.7 24.3 0.02 0.37 0.10 -0.001 <0.001 0.05 0.15 0.27 0.10 29.9 0.09 23.6 22.2 31.1 0.10	23.8 0.08	27.1 0.15	26.0 0.50 28.5 0.24 0.30 0.06		22.8 0.13 0.25 0.06	24.9 0.16	27.1 0.22	24.9 0.10	0.80 0.57	25.3 0.20	26.0 0.12	0.78 0.24
	Red meat
	(g/day) "Healthy" diet c -0.36 80.8	71.9 -0.01	0.16 76.7 78.8 0.001 -0.39 -0.21	73.4 0.06	0.76 71.7 78.9 78.3 0.52 0.01 -0.12 -0.20 -0.23 0.71	78.2 -0.15	76.3 -0.11	74.4 0.91 69.3 -0.29 0.57 0.00		83.3 0.11 -0.36 0.02 -0.20 -0.11 76.7 74.6	77.6 -0.24	0.95 0.74 -0.24 -0.13 75.5 77.1	0.80 0.33
	Processed Meat
	(g/day) Abbreviation: BMI: Body Mass Index. 49.5 47.9	0.66 50.2 54.0	41.9	0.02 46.7 44.6 54.8 0.22	49.0	55.0	42.2 0.07 41.3		56.1 0.01	48.7	46.2	51.2	0.69	48.4	49.0	0.87
	Fish (g/day)		37.5	42.3	0.48 32.5 37.6	49.6	0.13 38.7 36.5 44.4 0.76	39.2	44.9	35.6 0.61 46.0		33.8 0.20	44.0	40.0	35.8	0.61	41.2	38.6	0.71
	Dairy product
			285.1	306.1	0.43 275.6 294.0 317.4	0.47 306.8 294.0 286.1 0.83	318.8	302.2	265.9 0.38 282.0		309.3 0.46 322.1 247.4	317.5	0.07 288.8 302.5	0.60
	(g/day)
	Cake and biscuit
			56.6	56.4	0.98 59.7 59.5	50.4	0.48 59.3 55.8 54.5 0.85	52.2	45.6	71.7 0.06 64.4		48.6 0.11	53.7	62.1	53.7	0.62	59.9	53.1	0.33
	(g/day)
	Sugar and
	confectionery	50.4	42.9	0.23 42.6 49.8	47.5	0.64 49.2 53.9 36.9 0.22	48.6	51.4	40.0 0.49 52.4		40.9 0.18	49.8	52.4	37.7	0.23	54.9	38.4	0.01
	(g/day) a
	Fried product
			249.8	205.9	0.04 238.3 221.7 223.4 <0.001 217.6 212.1 253.8 0.75	229.0	224.4	230.1 0.07 224.8		230.8 0.01 244.1 232.8	206.6	0.14 228.7 226.9	0.05
	(g/day)
	Men Sweetened soft (g/day)	173.7	p* 217.1	[40-55[ vs [20-40[ 0.15 241.5 185.0 159.7 [55-73[ vs p* [20-40[	[25-30] vs <25 0.11 161.5 208.3 216.3 0.24 >30 vs <25 p*	Former smoker vs Non-193.8	Smoker vs Non-smoker 144.9 247.4 0.07 212.1 p* Yes vs No 178.7 0.43 199.8 188.4 p* CR vs No Extra-colic vs No 198.0	p* 0.95 219.7 171.1 Yes vs No	p* 0.11
	Alcohol drinks									smoker
	non (g/day) adherence vs	OR [IC] 120.0	OR [IC] 69.4 <0.001 92.5 85.7 105.8 OR [IC]	OR [IC] 0.41 89.7 92.4 102.0 0.82 OR [IC]	OR [IC] 78.1	OR [IC] 108.6	OR [IC] 97.5 0.08 102.3	87.1 0.41	OR [IC] 87.3 111.4 OR [IC] 85.5	0.29	OR [IC] 90.5 98.9	0.51
	adherence Coffee (ml/day)	192.9	166.8	0.17 166.5 176.2 196.9	0.44 193.4 171.4 174.8 0.51	144.5	195.9	199.2 0.02 206.4		153.3 0.05 185.7 190.4	163.4	0.58 158.8 200.9	0.03
	Carbohydrate		0.67	0.19	1.38	1.91	0.25	0.98	0.97	1.00	0.5	1.27	0.06	0.85	0.72	0.72		0.640	0.43	0.75	0.33
																				29

*

Acknowledgments

This study has been conducted using the AAS-Lynch study resource, the authors would like to thank all AAS-Lynch patients their cooperation to the study. We acknowledge the gastroenterologist and health staff for their collaboration and contribution in the study.

Data described in the manuscript, code book, and analytic code will be made available upon request pending approval.

The following persons are AAS-Lynch Study Group 2022: Robert Benamouzig, Florence Mary, Amal Aït Omar, Mourad Benallaoua, Noémie Demare, , Sabine Helfen,, Géraldine Perkins, Pierre Laurent-Puig, Jean-Christophe Saurin, Naouele Raby, Laurence Venat-Bouvet, Corinne Penaud, Delphine Bonnet, Virginie Sicart, Chloé Pomes, Thierry Lecomte, Claire Jollivet, Morgane Caulet, Stanislas Chaussade, Marion Dhooge, Fanny Maksimovic, Philippe Grandval, Sylvie Olschwang, Maud Saussereau, Jérôme Bellanger, Anne Netter-Coti, Hélène Delhomelle, Bruno, Lydia Mehdi, Sophie Lejeune, Afane Brahimi, Stéphane Cattan, Laurence Bellengier, David Tougeron, Sandrine Rafert, Emmanuelle Barouk Simonet, François Cornelis, Anna Serova-Erard, David Malka, Paul Gesta, Jeanne Oddoz, Véronique Mari, Samuel Lesourd, Gaëlle Kergoat, Louise Crivelli, Iradj Sobhani, Aurélien Amiot, Côme Lepage, Laurence Faivre-Olivier, Jean-Louis Jouve, Antoine Drouillard, Nora Perot, Bardou Marc, Sophie Nambot, Nadia Mekahli, Alain Governmental Drug agency (ANSM) authorization under the number 160223A-42 was obtained on June 10, 2016. Written informed consent to participate will be obtained from all study participants.

Declaration of competing interests:

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analysis, or interpretation of data; and in the writing of the manuscript.

Supplementary Methods -intended for publication

Supplementary table 1: Comparison of sociodemographic characteristics between patients with

Lynch syndrome from the AAS-Lynch study (n=276) and participants from the NutriNet-Santé study (n=547)