Prevalence of Pathogenic Germline Lineage Variants in DNA Repair by Race, Age, and Ethnicity in Men with Prostate Cancer

Chicago, IL (UroToday.com) Prostate cancer is one of the leading causes of cancer death in men and one of the most hereditary cancers. In the historical paper by Lichtenstein et al., 42% of the variation underlying prostate cancer could be explained by genetic factors.¹ This hereditary risk remains constant through the ages until the end of life.² Some variant alleles, such as HOXB13 G84E, can significantly increase the risk of prostate cancer, while other genes can predict the response to treatment with targeted therapies.^3.4 This summary provides the prevalence of pathogenic germline variants in DNA repair by race, age, and ethnicity in men with prostate cancer.

This abstract provides data on 3,057 men who were tested by Invitae for germ-line DNA in the United States. The majority of men were Caucasian (74%), but this study also provides data on a large cohort of African-Americans (229, 7%), a population in which there is little germline data. Also included in this badysis are 210 men (7%) who identified themselves as Ashkenazi Jews. Consistent with previous cohorts, 1.6% of men had the HOXB13 G84E gene variant, which significantly increases the risk of prostate cancer. In terms of mismatch repair genes (MSH2 / 6, MLH1, PMS2 and MUTYH), there was no significant difference in the overall prevalence of pathogenic mutations between Caucasian Americans, African Americans (AA), and Caucasians. Ashkenazi Jews (AJ). ) (CA 1.5% vs. AA 0.9% vs. AJ 1.4%, p = 0.89). There was also no difference in genes involved in the repair of homologous DNA (BRCA1 / 2, ATM, CHEK2, RAD51D and PALB2) between the three cohorts of patients.

Some studies have shown that younger patients are more likely to have a germline mutation, and the authors also examined this possibility and found no correlation between age at test and mutation prevalence. of the germ line. Finally, taking into account self-reported family history, there was no significant difference between the incidence of germline variants between those with and without a family.

In this extensive retrospective badysis of more than 3,000 men with prostate cancer and germline testing, there was no significant difference in the overall prevalence of actionable germline mutations, such as that mutations in the genes of MMR (immunotherapy) or HR (PARP inhibitors). Age at the time of testing and family history of self-reported prostate cancer were also badociated with the presence of a germline mutation. In summary, these data suggest that all men with advanced prostate cancer should be offered a germline test, which is consistent with current NCCN guidelines.

Presented by: Alexandria Mara, MD, Resident in Internal Medicine, Duke University School of Medicine

Written by: Jason Zhu, MD. Member of Duke University's Division of Hematology and Oncology, @TheRealJasonZhu, at the ASCO 2019 # ASCO19 Annual Meeting, May 31 to June 4, 2019, Chicago, United States

References:

1. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and hereditary causes of cancer – Cohort badyzes of twins from Sweden, Denmark and Finland. New England Journal of Medicine 2000; 343: 78-85.
2. Hjelmborg JB, Scheike T., Holst K, et al. The heritability of prostate cancer in the Nordic Twin Cancer Study. Cancer Epidemiology, Biomarkers and Prevention: publication of the American Association for Cancer Research, co-sponsored by the American Society of Preventive Oncology 2014; 23: 2303-10.
3. Mateo J, Carreira S, Sandhu S, et al. DNA Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine 2015; 373: 1697-708.
4. Ewing CM, Ray AM, Lange EM, et al. Germline mutations of HOXB13 and risk of prostate cancer. New England Journal of Medicine 2012; 366: 141-9.