Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

Abstract

Background & AimsRecent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study.MethodsWe performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.ResultsBoth positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.ConclusionsThe present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome–phenome archive (accession: EGAS00001002477).

The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

“…To account for confounding factors potentially influencing this observation, we investigated a potential relationship between the cMS length and our observed negative correlation. cMS length is a well-known factor influencing the likelihood of indel mutations on the observed mutation frequency 23 , 27 , 39 (Supplementary Fig. 5 ).…”

Colon Cancers Get a Negative (Selection) Attitude

“…Either alone or in aggregate, the negatively selected coding region mutants identified by Jonchere et al 1 were associated with significantly shorter disease-free survival. It is not clear whether the same will be the case for the majority of noncoding mutations, which likely will require larger cohorts to test effectively.…”

“…Together, the data from Jonchere et al 1 pose an interesting conundrum. The article provides clear evidence that negative selection occurs in colorectal cancer (CRC), or at least in MSI CRC.…”

“…Unfavorable (to the tumor) mutations could in principle simply be overcome by high genetic instability and positive selection in tumor evolution, but that would not explain the association with actually shorter survival curves. Thus, as Jonchere et al 1 proposed, there must be other compensatory mechanisms. Future studies uncovering these mechanisms potentially could define a previously unappreciated fundamental process that helps drive MSI CRC carcinogenesis.…”

Downregulation of ORP3 Correlates with Reduced Survival of Colon Cancer Patients with Advanced Nodal Metastasis and of Female Patients with Grade 3 Colon Cancer

“…Defective dMMR finally results in a strong mutator phenotype, indicated by microsatellite instability (MSI), which drives tumorigenesis. In MSI-driven tumorigenesis of CRC, positively, as well as negatively, selected driver gene mutations have been identified [12,13]. Approximately, 15% of CRC show high microsatellite instability (MSI-H) due to germline mutations in genes involved in DNA mismatch repair or somatic inactivation of the same signal pathway, often induced through hypermethylation of MLH1.…”