POLE somatic mutations in advanced colorectal cancer

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POLE somatic mutations in advanced colorectal cancer

Tuesday, 20.02.2018

Colorectal cancer (CRC) is one of the major causes of morbidity and mortality throughout the world. The etiological factors and pathogenic mechanisms underlying CRC development appear to be complex and heterogeneous. The majority of CRC cases occur sporadically, arising through the sequential accumulation of multiple genetic and/or epigenetic alterations involving genes that regulate cell growth and differentiation. Despite the huge progress in defining some of the common genetic and epigenetic alterations, the picture of somatic genetic changes in colorectal tumorigenesis is far from complete. To fill in the gaps, The Cancer Genome Atlas (TCGA) exome sequencing project published the result of full genomic profiling of 224 CRC samples. This work confirmed many previous mutational findings in CRC and additionally identified new rare findings, such as mutations in the exonuclease domain of polymerase, epsilon, catalytic subunit (POLE) gene in approximately 3% of sporadic microsatellite stable but hypermutated CRCs. To evaluate the role of POLE mutations in colorectal carcinogenesis, namely in advanced CRC, we searched for somatic mutations by Sanger sequencing in tumor DNA samples from 307 cases. Microsatellite instability and mutation analyses of a panel of oncogenes were performed in the tumors harboring POLE mutations. Three heterozygous mutations were found in two tumors, the c.857C>G, p.Pro286Arg, the c.901G>A, p.Asp301Asn, and the c.1376C>T, p.Ser459Phe. The p.Pro286Arg and the p.Ser459Phe were previously reported as somatic mutation hotspots and all these alterations are predicted to have a direct effect on the proofreading function. Of the POLE mutated CRC, one tumor was microsatellite stable and the other had low microsatellite instability, whereas KRAS and PIK3CA mutations were found in one tumor each. We conclude that POLE somatic mutations exist but are rare in advanced CRC, with further larger studies being necessary to evaluate its biological and clinical implications.

 

Authors and Affiliations:

Joana Guerra1, Carla Pinto1, Diana Pinto1, Manuela Pinheiro1, Romina Silva1, Ana Peixoto1, Patrícia Rocha1, Isabel Veiga1, Catarina Santos1, Rui Santos1, Verónica Cabreira1, Paula Lopes2, Rui Henrique2,3 and Manuel R. Teixeira1,3

1Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

2Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

3Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

 

Abstract:

Despite all the knowledge already gathered, the picture of somatic genetic changes in colorectal tumorigenesis is far from complete. Recently, germline and somatic mutations in the exonuclease domain of polymerase epsilon, catalytic subunit (POLE) gene have been reported in a small subset of microsatellite-stable and hypermutated colorectal carcinomas (CRCs), affecting the proofreading activity of the enzyme and leading to misincorporation of bases during DNA replication. To evaluate the role of POLE mutations in colorectal carcinogenesis, namely in advanced CRC, we searched for somatic mutations by Sanger sequencing in tumor DNA samples from 307 cases. Microsatellite instability and mutation analyses of a panel of oncogenes were performed in the tumors harboring POLE mutations. Three heterozygous mutations were found in two tumors, the c.857C>G, p.Pro286Arg, the c.901G>A, p.Asp301Asn, and the c.1376C>T, p.Ser459Phe. Of the POLE-mutated CRCs, one tumor was microsatellite-stable and the other had low microsatellite instability, whereas KRAS and PIK3CA mutations were found in one tumor each. We conclude that POLE somatic mutations exist but are rare in advanced CRC, with further larger studies being necessary to evaluate its biological and clinical implications.

 

Journal: Cancer Medicine

 

Link: http://onlinelibrary.wiley.com/doi/10.1002/cam4.1245/abstract;jsessionid=043454C4FCF9800C0BEDE710E403170F.f01t02?