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A polygenic risk score (PRS) for prostate cancer (PrCa) effectively identifies high-risk men, even those with type 2 diabetes mellitus (T2DM). Lower insulin-like growth factor-1 (IGF-1) may explain the reduced PrCa risk observed in T2DM patients.

Keywords:
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Area of Science:

  • Genetics and Epidemiology
  • Endocrinology
  • Oncology

Background:

  • Type 2 diabetes mellitus (T2DM) is linked to lower prostate cancer (PrCa) incidence.
  • The utility of a PrCa polygenic risk score (PRS) in stratifying risk among men with T2DM is not well-established.
  • Potential mediating roles of insulin-like growth factor-1 (IGF-1) and sex hormones in this association require investigation.

Purpose of the Study:

  • To determine if a PrCa PRS can predict PrCa risk independently of T2DM status.
  • To assess the interaction between PrCa PRS and T2DM status in relation to PrCa risk.
  • To explore the mediating effects of IGF-1 and sex hormones on the association between T2DM and PrCa risk.

Main Methods:

  • Analysis of over 140,000 men from the UK Biobank and Penn Medicine Biobank.
  • Construction of a PrCa PRS using genome-wide association study summary statistics.
  • Application of Cox proportional hazards models to evaluate PRS association with incident PrCa, adjusting for covariates and testing for T2DM interaction. IGF-1 and sex hormone levels were analyzed as potential mediators.

Main Results:

  • T2DM was associated with a reduced incidence of PrCa.
  • The PrCa PRS significantly predicted PrCa risk irrespective of T2DM status (p < 0.001).
  • Men with the highest PRS had the greatest risk, particularly those without T2DM. IGF-1 was positively associated with PrCa risk in both diabetic and non-diabetic men, while sex hormones showed no significant association in men with T2DM. Adjusting for testosterone and IGF-1 did not alter the PRS-PrCa association.

Conclusions:

  • A PrCa PRS is a valuable tool for risk stratification in men with and without T2DM, underscoring the role of genetic predisposition.
  • Lower IGF-1 levels in T2DM patients may partially explain the observed reduction in PrCa risk, suggesting a potential biological pathway.