Abstract
The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.
Highlights
Lynch Syndrome is caused by mutations in one out of four mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2 - and results in a 25% to 75% lifetime risk of colorectal cancer and 60% risk of endometrial cancer in women [1]
Subjects belonged to 29 families with a Lynch syndrome mismatch repair (MMR) pathogenic mutation, and all women carried the mutation
One familial MMR mutation in MSH6 (c.3729_3732dupATTA – p.(Phe1245Ilefs*31)) was a founder mutation common to nine subjects belonging to six families
Summary
Lynch Syndrome is caused by mutations in one out of four mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2 - and results in a 25% to 75% lifetime risk of colorectal cancer and 60% risk of endometrial cancer in women [1].Genetic testing helps estimating the individual risk, plan appropriate care, screening and prophylactic treatments. Lynch Syndrome is caused by mutations in one out of four mismatch repair (MMR) genes - MLH1, MSH2, MSH6 and PMS2 - and results in a 25% to 75% lifetime risk of colorectal cancer and 60% risk of endometrial cancer in women [1]. The risk to develop cancer conferred by a MMR mutation is modified by both the environment and genetic risk modifiers The identification of such genetic risk modifiers can improve risk prediction and genetic counseling, through the individualization of surveillance programs and the evaluation of benefits versus burdens associated with prophylactic strategies [1, 2]. The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call