Cancer Genomic Profiling in Colorectal Cancer: Current Challenges in Subtyping Colorectal Cancers Based on Somatic and Germline Variants

Abstract

Colorectal cancer (CRC) is a heterogeneous disease caused by the accumulation of multistep genetic alterations under the influence of genomic instability. Different backgrounds of genomic instability, such as chromosomal instability, microsatellite instability, hypermutated-single nucleotide variants, and genome stableinduced transformation in the colonic epithelium, can result in adenomas, adenocarcinomas, and metastatic tumors. Characterization of molecular subtypes and establishment of treatment policies based on each subtype will lead to better treatment outcomes and an improved selection of molecularly targeted agents. In Japan, cancer precision medicine has been introduced in the National Health Insurance program through the addition of the cancer genomic profiling (CGP) examination. It has also become possible to access a large amount of genomic information, including information on pathogenic somatic and germline variants, incomparable to conventional diagnostic tests. This information enables us to apply research data to clinical decision-making, benefiting patients and their healthy family members. In this article, we discuss the important molecules and signaling pathways presumed to be the driver genes of CRC progression and the signal transduction system in which they are involved. Molecular subtypes of CRC based on CGP examinations and gene expression profiles have been established in The Cancer Genome Atlas Network with the advent of next-generation sequencing technology. We will also discuss the recommended management of secondary/germline findings, pathogenic germline variants, and presumed germline pathogenic variants obtained from CGP examination and review the current challenges to better understand these data in a new era of cancer genomic medicine.

Clinical significance of the KRAS G13D mutation in anastomotic recurrence of colorectal cancer

“…KRAS is one of the key driver genes in CRC and is detected early in the carcinogenesis of CRC. The KRAS mutation rate in CRC is reported to be 30–40% worldwide, and KRAS codon 13 mutations, including KRAS G13D , are reported to occur in 6–8% of cases worldwide ( 11 – 13 ). In a large-scale study in Japan, the total KRAS mutation rate was 37.6%, and the KRAS codon 13 mutation rate was 7.7%, which was comparable to the results reported in Western countries ( 14 ).…”

“…The present study was conducted according to The Declaration of Helsinki and the study protocol was approved by the ethics committee of The University of Tokyo [approval no. 3252-( 13 )]. Informed consent was obtained in the form of an opt-out option on the website ( ).…”

“…The study protocol was approved by the ethics committee of The University of Tokyo [approval no. 3252-( 13 ); Tokyo, Japan]. This study was conducted in accordance with The Declaration of Helsinki.…”

Cancer-associated fibroblasts of colorectal cancer: Translational prospects in liquid biopsy and targeted therapy

“…CRC is a heterogeneous disease, and this influences patient prognosis and treatment efficacy (Xi and Xu, 2021). Genomic profiling on CRC has revealed the complex nature of this disease (Hinoi, 2021), which likely contributes to the patient's lack of response to therapy.…”