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 2-8 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 and POLE mutations in ∼15%, containing multiple frameshifted genes and BRAF(V600E); (2) nonhypermutated 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 microsatellite instability CRCs and some nonhypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in ∼60% that associates with metastatic behavior in both hypermutated and nonhypermutated 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.

Keywords: CIMP; Chromosomal Instability; Genomic Instability; Microsatellite Instability.

Figure 1

(A,B,C) Mutational landscape and characteristics of sporadic colorectal cancer (CRC). Based on the accumulated number of mutations within a CRC, tumors can be categorized as hypermutated or non-hypermutated. The pattern of gene mutations are different between the two categories, with a few of each as driver mutations in individual cancers. An additional category of “metastasis modulator” caused by EMAST is common after the cancer is formed.

Figure 2

Timeline for sporadic CRC pathogenesis and its characterized molecular pathways. (A) The timelines are based on the average age of CRC for each type. Tumorigenesis can be broken into tumor initiation (development of an adenoma), tumor progression that culminates in a malignancy (carcinoma) that can spread as metastasis. MSI-H tumors are known to have a shortened progression stage. (B) Each pathway has its feature of moving from normal to cancer and potentially metastasis, with varying histology. Wnt signaling is the gatekeeper for all 3 pathways. The CIMP pathway contributes to both the MSI-H (through hypermethylation of hMLH1) and CIN pathways, and specifically characterizes a serrated pathway. EMAST can modulate all three pathways.

Figure 3

(A) Schematic of the ERBB(EGFR)/KRAS/BRAF/MAPK signaling axis, and its connection with the PI3 Kinase pathway. Common sites for mutation in sporadic CRC are indicated. (B) COX and 15-PGDH reciprocal relationship. In sporadic CRCs, Cox-2 is elevated and 15-PGDH is diminished, increasing PGE2 levels that can mediate increased proliferation and angiogenesis. By blocking Cox-2 pharmacologically, and/or selecting patients with high expression of 15-PDGH, levels of PGE2 can be diminished which can help prevent both primary and recurrent CRC.

Figure 4

Outcomes of patients with sporadic CRC. (A) Matched phenotype with molecular pathways and patient outcome with sporadic CRC. Data abstracted from references #103 and #104. (B) Schematic on patient outcome modulation by EMAST. EMAST does not cause oncogenic transformation, but appears to be induced by inflammation that may modulate metastasis, affecting outcome.