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Invited Commentary
April 2017

Molecular Markers Beyond Microsatellite Instability for Assessing Prognosis in Early-Stage Colorectal Cancer: What Happens at Relapse?

Author Affiliations
  • 1Department of Hematology and Oncology, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
JAMA Oncol. 2017;3(4):481-482. doi:10.1001/jamaoncol.2016.5463

The knowledge of molecular abnormalities underlying colorectal tumorigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced by comprehensive sequencing studies.1 From genome-scale analyses we know that a handful of 24 genes are commonly affected by somatic mutations in colorectal cancer (CRC), whereas recurrent copy-number alterations and chromosomal translocations are much rarer in this disease. Although some of these molecular abnormalities result in genes acting as drivers of cancer progression, translation for therapeutic purposes is still very limited and encompasses only exclusion of RAS-mutated cancers from epidermal growth factor receptor–targeted treatment with monoclonal antibodies as the standard of care and targeted approaches for tumors with B-Raf proto-oncogene (BRAF) mutations and those amplified with v-erb-b2 leukemia viral oncogene homolog 2 (ERBB2 [formerly known as HER2]).2 However, CRC is probably the first cancer historically discovered to have subclasses with features so distinct that they could be considered as separate diseases. Approximately 15% of CRCs manifest a hypermutation phenotype, with a median number of 700 somatic mutations, and 75% of these tumors display a high frequency of the microsatellite instability (MSI-H) phenotype owing to mutation or inactivation of key proteins functioning in DNA mismatch repair (deficient MMR [dMMR]). These dMMR tumors can develop from an inherited germline mutation in an MMR gene (MutL protein homolog 1 [MLH1], MutS protein homolog 2 [MSH2], MutS protein homolog 2 [MSH6], and PMS homolog 2 [PMS2]), that is, Lynch syndrome, or more commonly owing to epigenetic inactivation of the MLH1 gene and the CpG island methylator phenotype. More important, the latter sporadic dMMR tumors carry somatic mutations in the BRAF oncogene in approximately half of cases. The remaining fraction of 25% CRCs with a hypermutation phenotype does not manifest the MSI-H phenotype and usually harbor somatic mutations in the gene encoding DNA repair polymerase ε or somatic mutations in the MMR pathways.1

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