Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance

Objective Estimates 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. Design We 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. Results 1942 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. Conclusions The 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. Significance of this study What is already known on this subject? ▸ Inherited colorectal cancer may be caused by mismatch repair gene mutations and is then commonly referred to as Lynch syndrome. ▸ Lynch syndrome is under-recognised and results in about 0.1% of the population having a significantly increased risk of early onset colorectal, endometrial and ovarian cancer. ▸ Endoscopic surveillance with removal of precursor adenomas is recommended to prevent colorectal cancer. What are the new findings? ▸ This is the first comprehensive prospective study to provide empirically observed data on colorectal cancer incidence and survival in Lynch syndrome. ▸ Colorectal cancer occurred despite colonoscopic surveillance with removal of adenomas. ▸ Colonoscopic surveillance with early detection and treatment of invasive colorectal cancer was associated with excellent survival. Survival after first endometrial or ovarian cancer was also excellent. ▸ Revised estimates of the different penetrance and expression patterns in carriers of MLH1, MSH2, MSH6 and PMS2 mutations. To cite: Møller P, Seppälä T, Bernstein I, et al. Gut 2017; 66:464–472 ► Additional material is published online only. To view please visit the journal online (h t t p : / / d x . d o i . o r g / 1 0 . 1 1 3 6 / g u t j n l 2 0 1 5 3 0 9 6 7 5 ) For numbered affiliations see end of article. Correspondence to Dr Pål Møller, Research Group Inherited Cancer, The Norwegian Radium Hospital, Oslo 0310, Norway; moller.pal@gmail.com Received 27 March 2015 Revised 6 November 2015 Accepted 17 November 2015 Published Online First 9 December 2015 Colon 464 Møller P, et al. Gut 2017;66:464–472. doi:10.1136/gutjnl-2015-309675 group.bmj.com on June 12, 2017 Published by http://gut.bmj.com/ Downloaded from