A Population-based Assessment of Germline HOXB13 G84E Mutation and Prostate Cancer Risk

130 Background: An inverse association has been shown between diabetes and prostate cancer risk. The aim of this study was to determine whether type 2 diabetes mellitus (T2DM) and metformin is associated with prostate cancer risk. Methods: A retrospective cohort design was used to examine the relationship between diabetes and prostate cancer risk. The cohort was composed of male patients identified with diagnosis of T2DM in the National Health Insurance Fund database during 2000–2016. Cancer cases were identified by record linkage with the Lithuanian Cancer Registry which is a nationwide population-based cancer registry that contains personal and demographic information, as well as information on diagnosis of all people diagnosed with cancer in Lithuania since 1978. We calculated standardized incidence ratios (SIRs) for prostate cancers as a ratio of observed number of cancer case in people with diabetes diagnosis to the expected number of cancer cases in the underlying general population. Results: Overall, 68,449 males were diagnosed with diabetes in Lithuania between 2000 and 2016 were included in final cohort. 2,754 prostate cancers were observed versus 3,111.26 expected within a period of observation entailing an SIR of 0.89 (95% CI: 0.85–0.92). Significantly lower risk of prostate cancer was found in diabetic patients in all age groups, there were no differences in prostate cancer risk by time since diabetes diagnosis. Significantly lower risk of prostate cancer also was found in both metformin users and never-users groups, with higher risk reduction in metformin users (SIR 0.71, 95% CI: 0.68–0.75) than in T2DM patients never-users (SIR 0.88, 95% CI: 0.80–0.96). Conclusions: In the large population-based study we found significantly decreased risk of prostate cancer among men with T2DM. Our study suggests that metformin use in patients with T2DM may be associated with reduced risk of developing prostate cancer.

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The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.67 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 67-67

Author(s):

Niedzica Camacho ◽

Athena Matakidou

Keyword(s):

Prostate Cancer ◽

Family History ◽

Cancer Risk ◽

Dna Damage Response ◽

Prostate Cancer Risk ◽

Population Based ◽

Uk Biobank ◽

Pathogenic Variants ◽

Whole Exome ◽

Damage Response

67 Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value < 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.

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