Details

Autor(en) / Beteiligte

• Chubb, Daniel
• Broderick, Peter
• Dobbins, Sara E
• Frampton, Matthew
• Kinnersley, Ben
• Penegar, Steven
• Price, Amy
• Ma, Yussanne P
• Sherborne, Amy L
• Palles, Claire
• Timofeeva, Maria N
• Bishop, D Timothy
• Dunlop, Malcolm G
• Tomlinson, Ian
• Houlston, Richard S

Titel

Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

Ist Teil von

• Nature communications, 2016-06, Vol.7 (1), p.11883-11883, Article 11883

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.