Abstract
The currently known Mendelian colorectal cancer (CRC) predisposition syndromes account for ∼5–10% of all CRC cases, and are caused by inherited germline mutations in single CRC predisposing genes. Using molecular inversion probes (MIPs), we designed a targeted next-generation sequencing panel to identify mutations in seven CRC predisposing genes: APC, MLH1, MSH2, MSH6, PMS2, MUTYH and NTHL1. From a consecutive series of 2,371 Chinese CRC patients, 140 familial and non-familial cases were selected that were diagnosed with CRC at or below the age of 35 years. Through MIP-based sequencing we identified pathogenic variants in six genes in 16 out of the 140 (11.4%) patients selected. In 10 patients, known pathogenic mutations in APC (five patients), MLH1 (three patients), or MSH2 (two patients) were identified. Three additional patients were found to carry novel, likely pathogenic truncating (n = 2) and missense (n = 1) mutations in the MSH2 gene and a concomitant loss of expression of both the MSH2 and MSH6 proteins in their respective tumor tissues. From our data, we conclude that targeted MIP-based sequencing is a reliable and cost-efficient approach to identify patients with a Mendelian CRC syndrome.
Highlights
Colorectal cancer (CRC; MIM 114500) is the third most common cancer in males and the second in females worldwide, with 1.2 million patients diagnosed annually [1]
Two autosomal recessive Mendelian colorectal cancer (CRC) syndromes have been described, namely MUTYH-associated polyposis (MAP) caused by biallelic mutations in the MUTYH gene and NTHL1-associated polyposis caused by biallelic mutations in the NTHL1 gene [4,5,6,7]
International criteria for hereditary CRC have been defined, such as the Amsterdam criteria I and II, the Bethesda guidelines and the Japanese standards, they are not suitable for small pedigrees, which are common in China
Summary
Colorectal cancer (CRC; MIM 114500) is the third most common cancer in males and the second in females worldwide, with 1.2 million patients diagnosed annually [1]. In China, CRC is the fifth most commonly diagnosed cancer and the fifth leading cause of cancer-related death among both men and women, with an estimated 376,300 new patients and 191,000 deaths in 2015. A family history of CRC or an early age at diagnosis are www.impactjournals.com/oncotarget indications for a genetic predisposition. Genetic factors are estimated to account for the development of ~30% of all CRCs [3]. Two autosomal recessive Mendelian CRC syndromes have been described, namely MUTYH-associated polyposis (MAP) caused by biallelic mutations in the MUTYH gene and NTHL1-associated polyposis caused by biallelic mutations in the NTHL1 gene [4,5,6,7]. A timely identification of individuals at a high risk to develop CRC allows presymptomatic screening and genetic counseling, which may lead to reductions in both morbidity and mortality [8, 9]
Sign-in/Register to view highlights & summary 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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
