PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organspecific cancer risks according to gene and gender and to determine survival after cancer. Methods: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 followup years. Results: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Background: Colonoscopy is one of the methods of choice for screening relatives of patients with colorectal cancer. Objective: To evaluate the rate of adherence to colonoscopy in first-degree relatives of patients with colorectal cancer and describe the lesions found. Methods: A prospective, cross-sectional, multicentre, nationwide study was conducted. The study population was composed of first-degree relatives of patients with colorectal cancer selected randomly from the EPICOLON study. Seventy-four index patients were included. These had 342 living first-degree relatives (parents, siblings and children), of whom 281 were interviewed. Results: The adherence rate was 38% (107/281). Adherence was greater in families with a higher degree of familial aggregation for colorectal cancer (88.9% for Amsterdam vs 33.3% for Bethesda and sporadic cancer; p,0.05), an index patient aged under 65 years (60% for patients ,65 years vs 32.9% for patients >65 years; p,0.05) and an index patient who was female (46.2% for women vs 31% for men; p = 0.28). Adherence was also greater in relatives under 65 years (54% in patients ,65 years vs 18% in patients >65 years; p = 0.05), in female relatives (49% in female relatives vs 27.3% in male relatives; p,0.05) and in siblings and children (40% in siblings and children vs 13% in parents; p,0.05). Lesions were found in 26% (28/107) of the study population. Nine (8.4%) individuals had a total of 18 advanced lesions. Conclusions: These results indicate that adherence to colonoscopy in our population of first-degree relatives was low. The adherence was more frequently associated with a higher degree of familial aggregation, a relative age of under 65 years, a sibling or offspring relationship, and female sex.

Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research.

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

Background and study aims Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions. Methods This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010-2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ± high definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed. Results From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ± 1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio [OR] 4.01 [95 % confidence interval 1.20-13.45]; P = 0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 [1.40-28.81]; P = 0.02) on baseline colonoscopy and the use of chromoendoscopy ± high definition endoscopy during reassessment colonoscopy (OR 4.99 [1.11-22.36]; P = 0.04). Conclusions A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.

BACKGROUND: Lynch syndrome (LS) is characterized by mismatch repair (MMR) deficiency. However, there is a group of patients where LS is suspected because of MMR deficiency but there is no germinal mutation in MMR genes.These patients are known as Lynch-like syndrome (LLS) and there is no consensus about their management. The aim of this study is to describe a large series of LLS patients and to analyze if there are clinical, pathology or molecular differences in patients with suspected hereditary or sporadic origin.METHODS: Patients with colorectal cancer (CRC) were included in a national registry when their tumors show immunochemical loss of MSH2, MSH6, PMS2 or loss of MLH1 with BRAF-wild type and/or no MLH1 methylation and absence of pathogenic mutation in these genes. Demographic, clinical and pathological variables, as well as family history of neoplasms were registered. RESULTS: We included 160 patients with LLS. Mean age at diagnosis of CRC was 55 years. A total of 66 patients were female (41%). Amsterdam I and II criteria were fulfilled by 11%, revised Bethesda guidelines by 65% of cases and 24% were diagnosed because of universal screening. There were no differences in sex, indication for colonoscopy, immunochemistry, pathology findings or personal history of CRC or other LS related tumors between patients fulfilling Amsterdam or Bethesda guidelines and patients diagnosed because of universal screening of LS without family history.

Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low. Personalized endoscopic surveillance based on polyp burden and advanced serrated histology could help to optimize prevention in patients with SPS.

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