Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

Abstract

ObjectiveEstimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.DesignWe undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.Results1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.ConclusionsThe four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Defining New Colorectal Cancer Syndromes in a Population-based Cohort of the Disease

“…Known cancer syndromes often involve an increased risk for a whole spectrum of tumours, such as CRC, endometrial, gastric, renal pelvis and other tumours in LS and breast cancer, leukemia, sarcoma, as well as brain tumours in LiFraumeni syndrome (12,13). Also, for the BRCA1, BRCA2 and APC genes and, in fact, almost all known cancer genes, a typical spectrum of different cancers is associated with each gene involved in the syndrome (14-16).…”

Colonoscopic surveillance – a cost-effective method to prevent hereditary and familial colorectal cancer

“…A large proportion of unknown PMS-2 carriers might cause an overestimation of both the expected cases of CRC in the cohort and the cost-effectiveness of surveillance. However, since PMS-2 seems to be the most rare MMR gene variant (5-10%), undiagnosed PMS-2 carriers would probably be very few with a low impact on the CRC estimations [29]. Another limitation is the small study population, although the statistical analysis indicates a significant reduction in CRC owing to surveillance.…”

“…Remaining QALYs in the study population as of the year they had their first colonoscopy 3893 Loss of QALYs due to the observed case of CRC with surveillance 3. studies suggest the risk for CRC in the most common HCRC syndrome -Lynch -is variable from 46% to 10%, depending on the associated MMR gene [29]. The MMR gene associated with the lowest risk for CRC is PMS-2, which was not tested during our study period.…”

Update on Hereditary Colorectal Cancer

“…The cumulative incidence of any cancer at 70 years of age is 72% for MLH1 and MSH2 mutation carriers but lower in MSH6 (52%) and PMS2 (18%) mutation carriers. MSH6 and PMS2 carriers developed no cancer before 40 years of age (4).…”

“…Heredity represents a major cause of CRC, with up to 30% of the cases estimated to develop due to genetic factors and about 5% linked to inherited mutations in cancerpredisposing genes (3). Identifying these high-risk patients is a major issue because morbidity and mortality from CRC and extracolonic cancer in patients and their relatives can be reduced by early and intensive screening (4,5).…”