ICARE Newsletter Winter 2015

Discovery of New Colorectal Cancer Genes

New inherited cancer genes continue to be discovered with the exciting advances made possible through next-generation sequencing technologies. Recent studies identified that the POL genes predispose to inherited colorectal cancer.1,2,3 In one study, Niemenen and colleagues studied a four-generation family with Lynch Syndrome with no evidence of mismatch repair deficiency.2 Through various means (including genetic linkage, exome sequencing, tumor studies, and functional investigations), they were able to identify a new gene called RPS20 which may be the underlying factor predisposing this family to colorectal cancer.

In another study, Palles and colleagues studied three large families with a dominant pattern of inherited colorectal cancer and multiple adenomas through whole genome sequencing.3 Through these efforts, they identified germline DNA polymerase gene mutations (i.e., POLE and POLD1) as high penetrance genes predisposing to multiple colorectal adenomas and early onset colorectal cancer. Subsequently, a Dutch study of 1188 patients with familial colorectal cancer and polyposis identified three patients with POLE mutations. These patients developed multiple colorectal adenomas, two of whom showed early onset colorectal cancer. Tumors from all three patients were microsatellite unstable and immunohistochemistry showed deficiency of MSH6/MSH2. These findings suggest evaluation of the POLE gene in microsatellite unstable colorectal cancers, especially when testing for other established Lynch syndrome gene mutations has not detected a mutation.

These advances serve to highlight the rapid pace at which new cancer genes continue to be identified. In addition to these new discoveries, next-generation sequencing technologies are also expected to make new testing options more quickly available. Consequently, it is important for individuals from high-risk families (particularly those with results that are ‘uninformative negative’ – i.e., where testing has not yet identified an inherited gene mutation) to periodically ask their healthcare providers whether additional testing options are available for them.

1. Elsayed FA, et al. European Journal of Human Genetics : EJHG. Nov 5 2014. 2. Nieminen TT, et al. Gastroenterology. Sep 2014;147(3):595-598 e595. 3. Palles C, et al. Nat Genet. Feb 2013;45(2):136-144.