Evolution of colorectal cancer: Change of pace and change of direction

Abstract

This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50 of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability).

Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas

“…[6][7][8][9] The underlying role of the MMR proteins in CRC was demonstrated when many of these genes, including MLH1, MSH2, MSH6 and PMS2, were discovered to be the cause of the Lynch syndrome (also known as HNPCC). The Lynch syndrome is associated with a 60-80% lifetime risk of CRC as well as with an increased risk of endometrial and genitourinary tract cancer.…”

Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer

“…is malignancy develops as a result of the transformation of normal colon epithelium to cancer via a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/ serrated adenomas [3,4]. Detection of early stage CRC and precancerous lesions has great promise to improve clinical outcomes and reduce mortality [5,6].…”

Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients

“…In HNPCC, mutations of APC, p53 and K-ras-2 genes and LOH of tumor-suppressor genes were significantly less frequent (P=0.03 or 0.0006), but transforming growth factor beta type II receptor mutation was significantly more frequent (P=0.000001) than those in non-HNPCC [7] . Summarized data from Jass [11] supported that the frequency of APC mutation was significantly lower in MSI-H colorectal tumors (39%, 36/92) and HNPCC (44%, 21/48) than in MSI-L (51%, 18/35) and MSS (58%, 241/417). However, the situation was quite different for 5q LOH in MSI-H tumors (3%;1/32) and HNPCC (10%;1/10), which were significantly less than MSI-L (47%;17/49) and MSS (57%;113/199).…”