24 Mar Genetic Variations Altering Familial Risk of Prostate Cancer Identified
MedicalResearch.com Interview with:
Jeffrey R. Smith, MD PhD
Department of Medicine, Division of Genetic Medicine
Vanderbilt-Ingram Cancer Center, and Vanderbilt Genetics Institute
Vanderbilt University Medical Center
Medical Research Service
Tennessee Valley Healthcare System, Veterans Administration
MedicalResearch.com: What is the background for this study?
Response: Roughly 20% of men with prostate cancer have a family history of the disease, and 5% meet criteria for hereditary prostate cancer. Although prostate cancer has the greatest heritability of all common cancers (twice that of breast cancer), extensive heterogeneity of its inherited causes has presented a considerable obstacle for traditional pedigree-based genetic investigative approaches. Inherited causes across, as well as within families are diverse.
This study introduced a new familial case-control study design that uses extent of family history as a proxy for genetic burden. It compared a large number of men with prostate cancer, each from a separate family with a strong history of the disease, to screened men with no personal or family history. The study comprehensively deconstructs how the 8q24 chromosomal region impacts risk of hereditary prostate cancer, introducing several new analytical approaches. The locus had been known to alter risk of prostate, breast, colon, ovarian, and numerous additional cancers.
MedicalResearch.com: What are the main findings?
Response: Seven distinct ancestral segments of DNA (haplotypes) were inherited among these men that alter risk of prostate cancer. Four haplotypes each carried risks as high as 22-fold, and three were instead protective. Each was distinguished by a large number of individual genetic variants that were associated with prostate cancer. Observations replicated across independent study populations and were at genome-wide significance. Sequencing the near-Mendelian haplotype revealed candidates for the causal mutation. One risk haplotype was associated with an early age of diagnosis, with a mean age that was seven years younger than the US and UK average. Intriguingly, haplotypes that were protective (reducing risk), were also associated with both a later age of diagnosis and less aggressive disease when inherited by a case.
MedicalResearch.com: What should readers take away from your report?
Response: Overall, the genetic variants discovered in the study account for ~ 9% of prostate cancer heritability. Study of cases with a strong history of the disease enabled the identification of genetic variation with particularly strong risk effects – with clinically predictive ability. The identified 8q24 risk-altering variants are pertinent for familial cancer care. The study introduces approaches that are effective in the setting of complex genetic heterogeneity and that discern risk from protective effects (both impacting a person’s risk).
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: The study design and analytical approaches can be applied to other, similarly complex diseases.
The authors report no conflicts of interest.
Dupont, W.D., Breyer, J.P., Plummer, W.D. et al. 8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer. Nat Commun 11, 1523 (2020). https://doi.org/10.1038/s41467-020-15122-1
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