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PLoS One. 2016 Dec 8;11(12):e0167847. doi: 10.1371/journal.pone.0167847. eCollection 2016.

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records.

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Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, United States of America.
Deparment of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Department of Biomedical Informatics, Columbia University Medical Center, New York, New York, United States of America.
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, United States of America.
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.



It is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes.


We analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes.


We demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery.

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Conflict of interest statement

K.W. was previously a board member and shareholder of Tute Genomics, Inc. Other authors declare no competing financial interests. There are no patents, products in development or marketed products to declare. This does not alter our adherence to the PLOS ONE policies. Due to participant privacy, the whole-genome sequencing data and their electronic health records studied in this paper cannot be shared with others.

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