Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer

Abstract

Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient’s genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations, and has classified new alterations. Each patient’s CRC is genetically unique, propelled by 2 to 8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a: (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability (MSI) and POLE mutations in ~15%, containing multiple frameshifted genes and BRAFV600E; (2) non-hypermutated group with multiple somatic copy number alterations and aneuploidy in ~85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes such as APC and TP53; (3) CpG Island Methylator Phenotype CRCs in ~20% that overlap greatly with MSI CRCs and some non-hypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in ~60% that associates with metastatic behavior in both hypermutated and non-hypermutated groups. Components from these classifications are now used as diagnostic, prognostic and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care.

A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway

“…The primary molecular pathways involved in CRC carcinogenesis are chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP), accounting for nearly 85, 15 and 10-40% of all sporadic cases, respectively [2,3]. CIN and MSI represent two levels of genetic instability, a subtle one affecting only DNA sequences, MSI-high (MSI-H), and a gross one, affecting portions or entire chromosomes, i.e., CIN.…”

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

“…Genotypes 1 and 2 (CIMP-high, consisting 20% of CRC cases) may miss APC mutation; opposite to this, APC loss characterizes genotypes 3 to 5 (8). Only half of the hypermutated colon cancers hold the mutation, percentage significantly lower compared to respective in the nonhypermutated ones (80%) (28). Moreover, experimental findings from transgenic mice showed that colorectal tumorigenesis can be initiated in the absence of APC or β-catenin mutation (29).…”

Studies of Malaysian Plants in Prevention and Treatment of Colorectal Cancer

“…The age-dependent increase in CRC development is associated with a multistep oncogenesis process and a number of histological stages, reflecting the accumulation of genetic errors in somatic cells over time. Sporadic CRC is currently thought to arise via 1 of 3 identified molecular pathways (Micro Satellite instability-MSI, Chromosomal Instability-CIN and CpG island methylator phenotype-CIMP) depending upon the individual's complement of gene alterations [13]. Conversely, the inheritance of germline mutations may also result in development of neoplasms at an early age, with approximately 5% of CRC cases being due to inherited single-gene syndromes such as familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) [14].…”