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Cancer Epidemiol Biomarkers Prev. 2019 Dec 11. doi: 10.1158/1055-9965.EPI-19-0887. [Epub ahead of print]

Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.

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Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.
Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire.
Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Québec, Canada.
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Mayo Clinic, Rochester, Minnesota.
Department of Medicine, University of Toledo Dana Cancer Center, Toledo, Ohio.
Mayo Clinic, Scottsdale, Arizona.
Baylor College of Medicine, Houston, Texas.
Medical College of Wisconsin, Milwaukee, Wisconsin.
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio.
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.



Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer.


Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected.


The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3.


Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes.


Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.

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