Abstract
A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps.
Highlights
A small minority of colorectal cancers (CRCs) (45%) are caused by a single, inherited faulty gene
Most of these predispose primarily to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1)
In some very rare individuals with congenital mismatch repair deficiency (CMMRD), who carry mutations in both copies of a Lynch syndrome gene (MSH2, MLH1, MSH6, PMS2), there is a predisposition to conventional adenomas
Summary
A small minority of colorectal cancers (CRCs) (45%) are caused by a single, inherited faulty gene. Most cases of colorectal cancer (CRC) arise as a result of somatic mutations in a stem-like cell somewhere in the epithelium of the large bowel. In a small minority of CRC patients, there is a strong genetic predisposition caused by a single faulty gene.[1,2,3,4,5] These diseases, the Mendelian CRC syndromes, have been important in furthering our understanding of colorectal carcinogenesis, and this work, in turn, has improved the management of these patients and their families.
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