Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes.
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.
1] Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA [2] Department of Biomedical Informatics, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Rachel D
0000000330899806
RD
Melamed
1] Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA [2] Department of Physics, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Kevin J
KJ
Emmett
Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Chioma
C
Madubata
1] Department of Medicine, University of Chicago, 900 E. 57th Street, Room 10160A, Chicago, Illinois 60637, USA [2] Computation Institute, University of Chicago, 900 E. 57th Street, Room 10160A, Chicago, Illinois 60637, USA [3] Institute for Genomics and Systems Biology, University of Chicago, 900 E. 57th Street, Room 10160A, Chicago, Illinois 60637, USA.
Andrey
A
Rzhetsky
1] Department of Systems Biology, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA [2] Department of Biomedical Informatics, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.
Raul
R
Rabadan
D015897:Comorbidity; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000453:epidemiology / Q000235:genetics*; D023281:Genomics; D006801:Humans; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*