Colorectal cancer and advanced adenoma characteristics according to causative mismatch repair gene variant in Japanese colorectal surveillance for Lynch syndrome.

BACKGROUND: The optimal interval of colonoscopy (CS) surveillance in cases with Lynch syndrome (LS), and stratification according to the causative mismatch repair gene mutation, has received much attention. To verify a feasible and effective CS surveillance strategy, we investigated the colorectal cancer (CRC) incidence at different intervals and the characteristics of precancerous colorectal lesions of LS cases. METHODS: This retrospective multicenter study was conducted in Japan. CRCs and advanced adenomas (AAs) in 316 LS cases with germline pathogenic variants (path_) were analyzed according to the data of 1,756 registered CS. RESULTS: The mean time interval for advanced CRCs (ACs) detected via CS surveillance was 28.7 months (95% confidence interval: 13.8-43.5). The rate of AC detection within (2.1%) and beyond 2 years (8.7%) differed significantly (p = 0.0003). AAs accounted for 43%, 46%, and 41% of lesions < 10 mm in size in the MLH1-, MSH2-, and MSH6-groups, respectively. The lifetime incidence of metachronous CRCs requiring intestinal resection for path_MLH1, path_MSH2, and path_MSH6 cases was 34%, 23%, and 14% in these cases, respectively. The cumulative CRC incidence showed a trend towards a 10-year delay for path_MSH6 cases as compared with that for path_MLH1 and path_MSH2 cases. CONCLUSIONS: In cases with path_MLH1, path_MSH2, and path_MSH6, maintaining an appropriate CS surveillance interval of within 2 years is advisable to detect of the colorectal lesion amenable to endoscopic treatment. path_MSH6 cases could be stratified with path_MLH1 and MSH2 cases in terms of risk of metachronous CRC and age of onset.

International consensus on the management of large (≥20 mm) colorectal laterally spreading tumors: World Endoscopy Organization Delphi study.

OBJECTIVES: There have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices. METHODS: Two experts in interventional endoscopy spearheaded an evidence-based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three-round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5-point Likert scale. RESULTS: Forty-two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision-making; seven statements on postresection evaluation; and eight statements on postresection care. CONCLUSIONS: An international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow-up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

Marital status after colorectal surgery in familial adenomatous polyposis: a nationwide multicenter study in Japan.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) experience psychological and social challenges concerning future events such as marriage and childbirth alongside the medical risks of colorectal cancer (CRC) and FAP-related disease. We retrospectively investigated the rate of marriage and childbirth postoperatively in Japanese patients with FAP. METHODS: We included 161 patients who had colorectal surgery and reported marital status from a national survey of 35 Japanese institutions. Participants were classified according to marital status: married before colectomy (80 patients), married after colectomy (13 patients), and unmarried (68 patients). RESULTS: The marriage rate for all 161 patients (57.8%, standardized ratio 0.95, 95% confidence interval [CI] 0.76-1.14) was comparable to that in the general Japanese population (57.1%). The marriage rate among the 81 patients who were unmarried before colectomy was low (16.0%); however, the standardized marital ratio (0.75, 95% CI 0.34-1.15) was not significantly lower than that of the general population. In multivariable logistic regression, younger age (born after 1980, odds ratio [OR] 0.12, p < 0.001) and genetic testing (OR 4.06, p = 0.001) were associated with postoperative marriage. Seventy-one percent of patients with FAP who married after colectomy became pregnant and achieved delivery. CONCLUSIONS: The marriage rate of patients with FAP was comparable to that of the general population whereas the rate after colectomy was low among patients with FAP. However, in patients with FAP, colorectal surgery itself may not lead to negative consequences in terms of fecundity.

Risk of metachronous colorectal cancer after surgical resection of index rectal cancer in Lynch syndrome: a multicenter retrospective study in Japan.

PURPOSE: This study evaluated the risk of metachronous colorectal cancer (CRC) after resection of index (first) rectal cancer in patients with Lynch syndrome (LS). METHODS: Clinicopathological data of patients with genetically proven LS were retrospectively analyzed in this multicenter Japanese study. The cumulative incidence of metachronous CRC and the overall survival were compared between patients with index rectal cancer (rectal group) and those with index colon cancer (colon group). RESULTS: The median age at index CRC surgery was lower in the rectal group than in the colon group (37 vs. 46 years old, P = 0.01). The cumulative 5-, 10-, and 20-year incidences of metachronous CRC were 3.5%, 13.9%, and 21.1%, respectively, in the rectal cancer group and 14.9%, 22.0%, and 57.9%, respectively, in the colon cancer group (P = 0.02). The overall survival curves were not significantly different between two groups (P = 0.23). CONCLUSION: This is the first report from an East Asian country to report the risk of metachronous CRC after resection of index rectal cancer in patients with LS. Despite this study having several limitations, we cannot recommend extended resection, such as total proctocolectomy, for index rectal cancer as a standard surgical treatment in patients with LS.

Efficacy of endoscopic submucosal resection with a ligation device for small rectal neuroendocrine tumor: study protocol of a multicenter open-label randomized control trial (BANDIT trial).

BACKGROUND: Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate. METHODS: This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study. DISCUSSION: This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

Risk of gastric adenoma and adenocarcinoma in patients with familial adenomatous polyposis in Japan: a nationwide multicenter study.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have an increased risk of developing gastric neoplasms. However, the clinical course of FAP with these gastric lesions has not yet been fully clarified. The present study aimed to clarify the changes in the incidence risk of developing gastric adenoma or gastric cancer during the lifespan of patients with FAP. METHODS: Four hundred forty-three patients with data regarding gastric adenoma and gastric cancer retrospectively registered in a nationwide Japanese multicenter study were enrolled. The cumulative incidences and hazard rates (HRs) of gastric neoplasms were evaluated. RESULTS: The cumulative incidence rates in 50-year-old patients with FAP were 22.8% for gastric adenoma and 7.6% for gastric cancer, respectively. No significant association was found between gastric neoplasms and the colonic phenotype. The peak age for the HR of gastric adenoma was 65 years, with the highest HR (0.043). Regarding the incidence of gastric cancer, the HR increased moderately up to the age of 40 years, but the increase accelerated from the age of 50 years (HR = 0.0067). CONCLUSION: Careful surveillance of the upper gastrointestinal tract in elderly patients with FAP, such as shortening the interval of follow-up according to age, may be helpful for early diagnosis of gastric cancer.

Performance evaluation of a computer-aided polyp detection system with artificial intelligence for colonoscopy.

OBJECTIVES: A computer-aided detection (CAD) system was developed to support the detection of colorectal lesions by deep learning using video images of lesions and normal mucosa recorded during colonoscopy. The study's purpose was to evaluate the stand-alone performance of this device under blinded conditions. METHODS: This multicenter prospective observational study was conducted at four Japanese institutions. We used 326 videos of colonoscopies recorded with patient consent at institutions in which the Ethics Committees approved the study. The sensitivity of successful detection of the CAD system was calculated using the target lesions, which were detected by adjudicators from two facilities for each lesion appearance frame; inconsistencies were settled by consensus. Successful detection was defined as display of the detection flag on the lesion for more than 0.5 s within 3 s of appearance. RESULTS: Of the 556 target lesions from 185 cases, detection success sensitivity was 97.5% (95% confidence interval [CI] 95.8-98.5%). The "successful detection sensitivity per colonoscopy" was 93% (95% CI 88.3-95.8%). For the frame-based sensitivity, specificity, positive predictive value, and negative predictive value were 86.6% (95% CI 84.8-88.4%), 84.7% (95% CI 83.8-85.6%), 34.9% (95% CI 32.3-37.4%), and 98.2% (95% CI 97.8-98.5%), respectively. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN000044622).

Short-term and long-term outcomes of submucosal dissection for residual or recurrent colorectal tumors after endoscopic resection: Analysis of a multicenter prospective study.

OBJECTIVES: We previously demonstrated that a favorable long-term prognosis indicated that endoscopic submucosal dissection (ESD) could be the standard treatment for large colorectal epithelial neoplasms, but the usefulness of ESD for local residual or recurrent tumors with submucosal fibrosis has not been fully demonstrated. The aim of the present study was to assess the usefulness of ESD for local residual or recurrent colorectal tumors. METHODS: We conducted a nationwide multicenter prospective study to evaluate the outcomes of ESD for colorectal tumors. In this post hoc analysis, a total of 54 local residual or recurrent colorectal tumors in 54 patients were included, and we analyzed the short-term and long-term outcomes of ESD for these lesions. RESULTS: The median size of the lesions was 16.0 (interquartile range [IQR] 11-25) mm. ESD was completed in 53 cases (98.1%) with a median procedure time of 65.0 min, but it was discontinued in one case because of submucosal cancer invasion. En bloc resection was achieved in 52 cases (96.3%), whereas R0 resection was achieved in 45 cases (83.3%). Intraoperative perforation was observed in four cases (7.4%) and delayed perforation in one (1.9%), but all cases could be managed conservatively. Delayed bleeding was not observed. There were no significant differences in short-term outcomes between the rectal and colonic lesions. There was no recurrence of the tumor during the median follow-up period of 60 (IQR 50-64) months. CONCLUSION: An analysis of our multicenter prospective study suggests that ESD is an effective salvage management for local residual or recurrent colorectal lesions.

Usefulness of genotyping APC gene for individualizing management of patients with familial adenomatous polyposis.

BACKGROUND: Colorectal polyp burden is crucial for the management of patients with familial adenomatous polyposis (FAP). However, accurate evaluation of polyp burden is difficult to standardize. This study aimed to examine the possible utility of genotype-oriented management of colorectal neoplasms in patients with FAP. METHODS: Clinicopathological data from genetically proven patients with FAP was analyzed using the database of a nationwide retrospective Japanese multicenter study. The cumulative incidence of CRC was evaluated between different genotype groups. Genotype-1 were defined as germline variants on attenuated FAP-associated regions (codons 1-177, alternative splice site of exon 10 (codon 312), 1581-2843) and Genotype-2 as the other variants. Weibull and Joinpoint analyses were performed to determine the annual percentage changes in CRC risk. RESULTS: Overall, 69 men and 102 women were included. Forty-eight patients underwent colorectal resection for the first CRC, and five patients underwent resection for first cancer in the remnant anorectal segment after prophylactic surgery. The 70-year cumulative incidence of CRC in all patients was 59.3%. Patients with Genotype-1 (n = 23) demonstrated a lower risk of CRC stages II-IV than those with Genotype-2 (n = 148, P = 0.04). The risk of stage II-IV CRC was estimated to increase markedly at the age of 49 years in the Genotype-1 patients and 34 years in the Genotype-2 patients, respectively. CONCLUSIONS: Different interventional strategies based on genotypes may be proposed for the clinical management of patients with FAP. This policy needs to be validated in further prospective studies focusing on long-term endoscopic intervention and optimal age at prophylactic (procto)colectomy.

Risk of metachronous colorectal cancer after colectomy for first colon cancer in Lynch syndrome: multicenter retrospective study in Japan.

BACKGROUND: We evaluated the risk of metachronous colorectal cancer (mCRC) and explored the optimal extent of colectomy in patients with Lynch syndrome (LS) and first colon cancer (fCC) in Japan, where the extent of colectomy for colon cancer (CC) is shorter than that in Western countries. METHODS: The clinicopathologic and survival data of patients with LS who developed CC were collected from a nationwide database and analyzed retrospectively. The cumulative incidence of mCRC after actual segmental colectomy was compared with that of mCRC when more extensive colectomy was assumed. RESULTS: There were 142 eligible patients (65 female). The median age at fCC surgery was 46.5 (range: 14-80) years. The cumulative incidence of 5-, 10-, and 20-year mCRC rate was 13.4%, 20.8%, and 53.6%, respectively. The incidence was higher in the left-sided group (splenic flexure to rectosigmoid colon, n = 54) than in the right-sided group (cecum to transvers colon, n = 88) (66.3% vs. 45.3% in 20 years, P < 0.01). Assuming that all patients would have undergone hemicolectomy or total colectomy, the estimated mCRC risk was 41.5% and 9.4% (P < 0.01, vs. actual procedures), respectively. The 20-year overall survival rate of all the patients was 83.3% without difference by fCC sidedness (P = 0.38). CONCLUSIONS: To reduce the incidence of mCRC, patients with genetically diagnosed LS and fCC, preferentially located in the left-sided colon, may need to undergo more extended colectomy than that usually performed in Japan. However, such extended colectomy should be counterbalanced with favorable overall survival and actual risk of mCRC development.

Adding Induction Chemotherapy Before Chemoradiotherapy with Total Mesorectal Excision and Selective Lateral Lymph Node Dissection for Patients with Poor-Risk, Locally Advanced, Mid-to-Low Rectal Cancer May Improve Oncologic Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate whether the addition of induction chemotherapy before chemoradiotherapy (CRT) and total mesorectal excision (TME) with selective lateral lymph node dissection improves disease-free survival for patients with poor-risk, mid-to-low rectal cancer. METHODS: The authors' institutional prospective database was queried for consecutive patients with clinical stage II or III, primary, poor-risk, mid-to-low rectal cancer who received neoadjuvant treatment followed by TME from 2004 to 2019. The outcomes for the patients who received induction chemotherapy before neoadjuvant CRT (induction-CRT group) were compared (via log-rank tests) with those for a propensity score-matched cohort of patients who received neoadjuvant CRT without induction chemotherapy (CRT group). RESULTS: From 715 eligible patients, the study selected two matched cohorts with 130 patients each. The median follow-up duration was 5.4 years for the CRT group and 4.1 years for the induction-CRT group. The induction-CRT group had significantly higher rates of 3-year disease-free survival (83.5 % vs 71.4 %; p = 0.015), distant metastasis-free survival (84.3 % vs 75.2 %; p = 0.049), and local recurrence-free survival (98.4 % vs 94.4 %; p = 0.048) than the CRT group. The pathologically complete response rate also was higher in the induction-CRT group than in the CRT group (26.2 % vs 10.0 %; p < 0.001). Postoperative major complications (Clavien-Dindo classification ≥III) did not differ significantly between the two groups (12.3 % vs 10.8 %; p = 0.698). CONCLUSIONS: The addition of induction chemotherapy to neoadjuvant CRT appeared to improve oncologic outcomes significantly, including disease-free survival, for the patients with poor-risk, mid-to-low rectal cancer who underwent TME using selective lateral lymph node dissection.

Risk Factors for Lymph Node Metastasis of Rectal Neuroendocrine Tumor and Its Prognostic Impact: A Single-Center Retrospective Analysis of 195 Cases with Radical Resection.

PURPOSE: The incidence of rectal neuroendocrine tumors (NETs) has been steadily increasing. The risk factors for and prognostic impact of lymph node (LN) metastasis were analyzed in 195 patients with stage I-III rectal NET who underwent radical surgery. METHODS: This retrospective, single-center study analyzed risk factors for LN metastasis focusing on previously identified factors and a novel risk factor: multiple rectal NETs. The association between LN metastasis and the prognosis was also analyzed. RESULTS: Pathologically, the LN metastasis rate (also the rate of stage III disease) was 39%, which was higher than the clinical LN metastasis rate of 14%. Tumor size > 10 mm, presence of central depression, tumor grade G2, depth of invasion, LN swelling on preoperative imaging (cN1), venous invasion and multiple NETs were identified as risk factors for LN metastasis. As the tumor size and risk factors increased, the rate of LN metastasis increased. Among these 7 factors, venous invasion, cN1, and multiple NETs were identified as independent predictors of LN metastasis. LN metastasis of rectal NETs was associated with significantly poor disease-free and disease-specific survival. CONCLUSIONS: As risk factors increase, the potential for rectal NETs to metastasize to the LNs increases and LN metastasis is associated with a poor prognosis. This is the first study to report multiple NETs as a risk factor for LN metastasis. A future study examining the survival benefit of radical surgery accompanying LN dissection compared with local resection is warranted.

Current practice of colonoscopy surveillance in patients with lynch syndrome: A multicenter retrospective cohort study in Japan.

Objectives: Colonoscopy surveillance reduces the incidence of colorectal cancer through the detection and endoscopic removal of adenomas. Current guidelines recommend that patients with Lynch syndrome should have colonoscopy surveillance every 1-2 years starting at the age of 20-25. However, insufficient data are available to evaluate the quality and safety of colonoscopy surveillance for patients with Lynch syndrome nationwide in Japan. Methods: Patients with Lynch syndrome (n = 309) from 13 institutions who underwent one or more colonoscopy procedures were enrolled in this retrospective analysis. Colonoscopy completion rate, colonoscopy-related complication rate, proportion with an adequate colonoscopy interval, and adenoma detection rate were reviewed. Results: The colonoscopy completion rate was 98.8% and a history of previous colorectal cancer surgery was significantly associated with a higher completion rate. All complications were associated with endoscopic treatment and the rate of bleeding needing hemostasis and perforation needing surgical repair were both 0.16% after colonoscopy with polypectomy. The adenoma detection rate at the first colonoscopy was 25%. Although there was no difference in the completion and complication rates based on differences in the colonoscopy experience of the endoscopist, the detection rate of adenomas and intramucosal cancers was significantly higher with more experienced endoscopists. The proportion of patients developing cancer was significantly higher with a >24 months than a ≤24 months interval. Conclusion: High-volume experienced endoscopists and appropriate surveillance intervals may minimize the risk of developing colorectal cancers in patients with Lynch syndrome.

Long-term Outcomes After Endoscopic Submucosal Dissection for Large Colorectal Epithelial Neoplasms: A Prospective, Multicenter, Cohort Trial From Japan.

BACKGROUND & AIMS: To determine the long-term outcomes after colorectal endoscopic submucosal dissection (ESD), we conducted a large, multicenter, prospective cohort trial with a 5-year observation period. METHODS: Between February 2013 and January 2015, we consecutively enrolled 1740 patients with 1814 colorectal epithelial neoplasms ≥20 mm who underwent ESD. Patients with noncurative resection (non-CR) lesions underwent additional radical surgery, as needed. After the initial treatment, intensive 5-year follow-up with planned multiple colonoscopies was conducted to identify metastatic and/or local recurrences. Primary outcomes were overall survival, disease-specific survival, and intestinal preservation rates. The rates of local recurrence and metachronous invasive cancer were evaluated as the secondary outcomes. RESULTS: The 5-year overall survival, disease-specific survival, and intestinal preservation rates were 93.6%, 99.6%, and 88.6%, respectively. Patients with CR lesions had no metastatic occurrence, and patients with non-CR lesions had 4 metastatic occurrences. Kaplan-Meier curves revealed that overall survival and disease-specific survival rates were significantly higher in patients with CR lesions than in those with non-CR lesions (P > .001 and P = .009, respectively). Local recurrence occurred in only 8 lesions (0.5%), which were successfully resected by subsequent endoscopic treatment. Multiple logistic regression analyses revealed that piecemeal resection (hazard ratio, 8.19; 95% CI, 1.47-45.7; P = .02) and margin-positive resection (hazard ratio, 8.06; 95% CI, 1.76-37.0; P = .007) were significant independent predictors of local recurrence after colorectal ESD. Fifteen metachronous invasive cancers (1.0%) were identified during surveillance colonoscopy, most of which required surgical resection. CONCLUSIONS: A favorable long-term prognosis indicates that ESD can be the standard treatment for large colorectal epithelial neoplasms. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000010136.

Efficacy of the pocket-creation method with a traction device in endoscopic submucosal dissection for residual or recurrent colorectal lesions.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) for residual or recurrent colorectal lesions after incomplete resection is challenging because of severe fibrosis. This study aimed to compare the efficacy of the pocket-creation method (PCM) with a traction device (TD) with that of conventional ESD for residual or recurrent colorectal lesions. METHODS: We retrospectively studied 72 patients with residual or recurrent colorectal lesions resected using ESD. Overall, 31 and 41 lesions were resected using PCM with TD and conventional ESD methods, respectively. We compared patient background and treatment outcomes between the PCM with TD and conventional ESD groups, respectively. The primary endpoints were en bloc resection and R0 resection rates. The secondary endpoints were the dissection speed and incidence of adverse events. RESULTS: En bloc resection was feasible in all cases with PCM with TD, but failed in 22% of cases of conventional ESD. The R0 resection rates for PCM with TD and conventional ESD were 97% and 66%, respectively. Dissection was significantly faster in the PCM with TD group (13.0 vs. 7.9 mm2/min). Perforation and postoperative bleeding were observed in one patient in each group. CONCLUSION: PCM with TD is an effective method for treating residual or recurrent colorectal lesions after incomplete resection.

Risk of first onset of colorectal cancer associated with alcohol consumption in Lynch syndrome: a multicenter cohort study.

BACKGROUND: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. METHODS: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. RESULTS: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). CONCLUSIONS: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.