Genetic and nongenetic mechanisms for colorectal cancer evolution

Abstract

The stepwise accumulation of key driver mutations is responsible for the development and malignant progression of colorectal cancer in primary sites. Genetic mouse model studies have revealed combinations of driver gene mutations that induce phenotypic changes in tumors toward malignancy. However, cancer evolution is regulated by not only genetic alterations but also nongenetic mechanisms. For example, certain populations of metastatic cancer cells show a loss of malignant characteristics even after the accumulation of driver mutations, and such cells are eliminated in a negative selection manner. Furthermore, a polyclonal metastasis model has recently been proposed, in which cell clusters consisting of genetically heterogeneous cells break off from the primary site, disseminate to distant organs, and develop into heterogenous metastatic tumors. Such nongenetic mechanisms for malignant progression have been elucidated using genetically engineered mouse models as well as organoid transplantation experiments. In this review article, we discuss the role of genetic alterations in the malignant progression of primary intestinal tumors and nongenetic mechanisms for negative selection and polyclonal metastasis, which we learned from model studies.

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…MSI, on the other hand, is characterized by a high frequency of mutations in short repetitive DNA sequences, primarily due to defects in the DNA mismatch repair system. MSI-high tumors are more responsive to immunotherapies due to their increased mutational load. , …”

Advances and Challenges in Targeted Therapy for Colorectal Cancer: A Focus on Adenomatous Polyposis Coli and Kirsten Rat Sarcoma Virus Mutations

“…The APC gene holds substantial importance as a frequently mutated tumor suppressor gene within CRC. 10 Situated on chromosome 5q21-q22, this gene spans 8535 nucleotides and comprises 21 exons encoding a 310 kDa protein containing 2843 amino acids. A pivotal site for both germline and somatic mutations of APC lies within exon 15, encompassing 75% of the gene's coding sequence.…”

“…18, 19 Evidently, APC intricately interacts with critical signaling pathways and biological processes implicated in CRC development. 10 Recent investigations have shown that restoring APC functionality can promote tumor regression and restore crypt homeostasis in CRC, suggesting that the Wnt pathway is a promising therapeutic target for CRC treatment. 20…”