Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability.
Background & Aims
Recent 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.


Methods
We 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.


Results
Both 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.


Conclusions
The 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).
['Jonchere|Vincent|V|', 'Marisa|Laetitia|L|', 'Greene|Malorie|M|', 'Virouleau|Alain|A|', 'Buhard|Olivier|O|', 'Bertrand|Romane|R|', 'Svrcek|Magali|M|', 'Cervera|Pascale|P|', 'Goloudina|Anastasia|A|', 'Guillerm|Erell|E|', 'Coulet|Florence|F|', 'Landman|Samuel|S|', 'Ratovomanana|Toky|T|', 'Job|Sylvie|S|', 'Ayadi|Mira|M|', 'Elarouci|Nabila|N|', 'Armenoult|Lucile|L|', 'Merabtene|Fatiha|F|', 'Dumont|Sylvie|S|', 'Parc|Yann|Y|', 'Lefèvre|Jérémie H|JH|', 'André|Thierry|T|', 'Fléjou|Jean-François|JF|', 'Guilloux|Agathe|A|', 'Collura|Ada|A|', 'de Reyniès|Aurélien|A|', 'Duval|Alex|A|']
D000818:Animals D001483:Base Sequence D063646:Carcinogenesis D045744:Cell Line, Tumor D015331:Cohort Studies D015179:Colorectal Neoplasms D005260:Female D064593:Heterografts D006801:Humans D008297:Male D051379:Mice D008819:Mice, Nude D053842:Microsatellite Instability D015233:Models, Statistical D009154:Mutation D012091:Repetitive Sequences, Nucleic Acid D000073359:Whole Exome Sequencing
Positive and Negative Selection Colorectal Cancer Microsatellite Instability Tumorigenic Process CRC, colorectal cancer Driver Gene Mutations HR, hazard ratio MLH1, MutL Homolog 1 MMR, mismatch repair MSH, MutS Homolog MSI, microsatellite instability NR, nonrepetitive PBS, phosphate-buffered saline PCR, polymerase chain reaction R, repetitive RFS, relapse-free survival RTCA, Real-Time Cell Analyzer UTR, untranslated region WES, whole-exome sequencing WGA, whole-genome amplification bp, base pair indel, insertion/deletion mRNA, messenger RNA shRNA, short hairpin RNA siRNA, small interfering RNA