Cellular and Molecular Gastroenterology and Hepatology (Jan 2018)

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

  • Vincent Jonchere,
  • Laetitia Marisa,
  • Malorie Greene,
  • Alain Virouleau,
  • Olivier Buhard,
  • Romane Bertrand,
  • Magali Svrcek,
  • Pascale Cervera,
  • Anastasia Goloudina,
  • Erell Guillerm,
  • Florence Coulet,
  • Samuel Landman,
  • Toky Ratovomanana,
  • Sylvie Job,
  • Mira Ayadi,
  • Nabila Elarouci,
  • Lucile Armenoult,
  • Fatiha Merabtene,
  • Sylvie Dumont,
  • Yann Parc,
  • Jérémie H. Lefèvre,
  • Thierry André,
  • Jean-François Fléjou,
  • Agathe Guilloux,
  • Ada Collura,
  • Aurélien de Reyniès,
  • Alex Duval

Journal volume & issue
Vol. 6, no. 3
pp. 277 – 300

Abstract

Read online

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). Keywords: Colorectal Cancer, Microsatellite Instability, Tumorigenic Process, Driver Gene Mutations, Positive and Negative Selection