Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q
- 1 February 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 29 (2), 434-442
- https://doi.org/10.1158/1055-9965.epi-19-0887
Abstract
Background: 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. Methods: Parametric genetic linkage analysis was performed on these samples using two distinct analyses - the lung cancer only (LCO) analysis, where only lung cancer patients were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. Results: 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. is a significant eQTL 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. Conclusions: 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. Impact: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.Funding Information
- NIH NCI (U01CA76293)
- NIH NCI (U19CA148127)
- NIH NCI (P30CA22453)
- NIH NCI (R03CA77118)
- NIH NCI (R01CA80127)
- NIH NCI (R01CA84354)
- NIH National Institute of Environmental Health Sciences (P30ES006096)
- Department of Health and Human Services (HHSN26820100007C)
- Department of Health and Human Services (HHSN268201700012C)
- CPRIT (RR170048)
This publication has 64 references indexed in Scilit:
- Annotation of functional variation in personal genomes using RegulomeDBGenome Research, 2012
- SIFT web server: predicting effects of amino acid substitutions on proteinsNucleic Acids Research, 2012
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- Two members of the SIBLING family of proteins, DSPP and BSP, may predict the transition of oral epithelial dysplasia to oral squamous cell carcinomaCancer, 2010
- Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramificationsClinical Genetics, 2009
- Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1Nature Genetics, 2008
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics, 1995