Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Abstract

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.

Primary malignant pericardial tumour in Lynch syndrome

“…Among LS patients, the majority of those developing extraintestinal malignancies are MSH2 mutation carriers [10,11]. Recent studies have shown that LS patients may present different neoplastic formations according to age, gender and type of MMR defect [3,4]. Furthermore, a worse prognosis has emerged among the elderly [4].…”

“…It is estimated that 1 in 279 people carry mutations in DNA mismatch repair genes [2]. Patients with MMR gene mutations have a significantly increased risk for cancer [3,4]; indeed, LS is the most common inherited colorectal susceptibility syndrome, accounting for approximately 3% of newly diagnosed cases of colorectal cancer and 3% of cases of endometrial cancer [5]. Although the predominant malignancies are colorectal and endometrial cancer, a wide variety of malignancies is reported, with sites including ovary, upper urinary tract, stomach, small bowel, pancreas, biliary tract, skin, and brain [6].…”

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

“…Variability in results may reflect different methods of ascertainment, cohort sizes, ethnicity, or other factors. In the large multicenter prospective investigation by Dominguez-Valentin et al [5], the cumulative risk of breast cancer to 75 years of age was 12-15%, similar across all four MMR genes and representing only a marginal increase vs. average population.…”

“…studies, recent prospective studies have arrived at somewhat lower age-specific risk estimates for cancers occurring in MMR variant carriers; moreover, penetrance and expression patterns greatly depend on the MMR gene involved [5]. Among individual MMR genes, pathogenic variants in MLH1 and MSH2 have the highest and PMS2 the lowest penetrance, and MSH6 variants underlie a sex-limited trait with a high risk of gynecological cancers in females [5].…”

Harveian Oration 2019: Prediction and prevention in the genomic era

“…Those with defects involving the two main genes, MSH2 and MLH1, have a 75% probability of developing one or more of the cancers before they reach old age. 45 In 2017, the National Institute for Health and Care Excellence (NICE) announced that all colorectal cancers should be checked for evidence of mismatch repair deficiency in order to help identify families with LS. They were impressed by the clear evidence of benefit.…”