Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes

Rachel D. Melamed, Kevin J. Emmett, Chioma Madubata, Andrey Rzhetsky and Raul Rabadan ()
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Rachel D. Melamed: Columbia University
Kevin J. Emmett: Columbia University
Chioma Madubata: Columbia University
Andrey Rzhetsky: University of Chicago
Raul Rabadan: Columbia University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Despite large-scale cancer genomics studies, key somatic mutations driving cancer, and their functional roles, remain elusive. Here, we propose that analysis of comorbidities of Mendelian diseases with cancers provides a novel, systematic way to discover new cancer genes. If germline genetic variation in Mendelian loci predisposes bearers to common cancers, the same loci may harbour cancer-associated somatic variation. Compilations of clinical records spanning over 100 million patients provide an unprecedented opportunity to assess clinical associations between Mendelian diseases and cancers. We systematically compare these comorbidities against recurrent somatic mutations from more than 5,000 patients across many cancers. Using multiple measures of genetic similarity, we show that a Mendelian disease and comorbid cancer indeed have genetic alterations of significant functional similarity. This result provides a basis to identify candidate drivers in cancers including melanoma and glioblastoma. Some Mendelian diseases demonstrate ‘pan-cancer’ comorbidity and shared genetics across cancers.

Date: 2015
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DOI: 10.1038/ncomms8033

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