Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer-Specific Polygenic Scores

Our plain-English summary of Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer-Specific Polygenic Scores, by B. Prassas, Z. Shi, H. Tran, et al (Cancer Medicine, 2025).

The study

• Authors: B. Prassas, Z. Shi, H. Tran, J. Wei, C.H. Wang, A.S. Rifkin, A. Ashworth, S.L. Zheng, A.J. Mulford, A.R. Sanders, C.E. Pesce, B.T. Helfand, H.M. Dunnenberger, D. Duggan, P.J. Hulick, A. DePersia, J. Xu
• Journal: Cancer Medicine
• Published: 2025;14(11):e70990
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: BRCA2 is a causal gene for hereditary breast and ovarian cancer (HBOC) syndrome. However, its association with other cancers and interplay with polygenic scores (PGS) remains unclear.

Methods: An observational cohort study for the diagnosis of various cancers in the UK Biobank (UKB, N = 453,541) were recruited at ages of 40-69 years Association of germline pathogenic variants (PVs) in BRCA2 and published cancer-specific PGS with cancer risk was tested using Cox proportional hazards model.

Results: The median age and interquartile range (IQR) of participants at the analysis was 58.34 (50.60-63.74) years. Carriers of BRCA2 PVs (N = 1629) had a significantly increased risk for four core HBOC-associated cancers (breast, ovarian, pancreatic, and prostate) and six additional types of cancer (lung, oral, small intestine, larynx, liver, and mesothelioma), hazard ratio (HR) > 2.37, all ps < 0.001. For eight cancers where cancer-specific PGS is available, each PGS was significantly associated with its respective cancer risk and independent of BRCA2, HR > 1.25 for 1 unit increase in standard deviation, all ps < 0.001. For female breast and prostate cancer, a significant interaction between BRCA2 and PGS was found (HR < 0.83, p < 0.05); the effect of PGS on cancer risk was weaker in carriers than noncarriers. The probability of cancer by age 75 years (P75) for these 10 cancers increased with higher PGS deciles in both carriers and noncarriers. For several cancers, the P75 in carriers with the lowest PGS decile was lower than that of noncarriers with the highest PGS decile.

Conclusions: BRCA2 PVs increase risk beyond core HBOC cancers and their risks are modified by cancer-specific PGS. These results suggest that genetic counseling of BRCA2 PV carriers may extend to cancers beyond core HBOC syndrome and incorporate cancer-specific PGS in estimating their penetrance.

© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.

In plain English

This study analysed genetic and cancer records of 453,541 UK Biobank participants recruited at ages 40 to 69. It asked which cancers are linked to inherited harmful (pathogenic) variants in the BRCA2 gene, and how a polygenic score, which combines many common genetic variants, changes those risks. The authors found 1,629 carriers (0.36%). Carriers had a higher risk of any cancer (hazard ratio 2.29, 95% CI 2.12 to 2.47). Besides breast, ovarian, pancreatic and prostate cancer, carriers had significantly higher risk of six other cancers. The article labelled one of them mesothelioma but defined it by disease codes C45 to C49, a range not limited to mesothelioma. This group included 22 of 1,629 carriers (1.35%) and 1,580 of 451,912 noncarriers (0.35%), hazard ratio 4.17 (2.73 to 6.35). It had no polygenic score analysis. For cancers with a score, higher scores went with higher risk in carriers and noncarriers alike. The authors cautioned that the six newly linked cancers could be false positives because few carriers had them. The article does not discuss asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Population-based cohort study (analysis of UK Biobank data) using Cox proportional hazards models
• Who was studied: 453,541 UK Biobank participants with genetic data, aged 40 to 69 at recruitment, from across the United Kingdom. Median age at recruitment was 58.34 years; 93.93% were of European ancestry and 54.23% were female. Cancer diagnoses were followed up to June 12, 2023.
• Exposure: Inherited pathogenic or likely pathogenic variants in the BRCA2 gene, found by whole exome sequencing (1,629 carriers), and published cancer-specific polygenic scores. No asbestos or other occupational exposure was studied.
• Main results:
  • Any cancer: 41.80% of carriers versus 22.39% of noncarriers; hazard ratio 2.29 (95% CI 2.12 to 2.47).
  • Core hereditary breast and ovarian cancer (HBOC) cancers in carriers: hazard ratio 4.89 (4.32 to 5.54) for female breast, 15.42 (7.20 to 33.01) for male breast, 10.89 (8.56 to 13.85) for ovarian, 3.57 (2.30 to 5.55) for pancreatic and 2.37 (1.98 to 2.85) for prostate cancer.
  • Six further cancer groups were significantly more common in carriers: larynx (HR 3.89), liver (HR 3.17), lung (HR 2.69), the group the article labels mesothelioma (HR 4.17), oral (HR 2.80) and small intestine (HR 3.90), all p less than 0.001.
  • The category labelled mesothelioma was defined by ICD-10 codes C45 to C49, a range not limited to mesothelioma. It included 1,580 of 451,912 noncarriers (0.35%) and 22 of 1,629 carriers (1.35%); hazard ratio 4.17 (2.73 to 6.35). The article does not say how many of these cases were mesothelioma itself.
  • Estimated probability of female breast cancer by age 75 among carriers was 35.54% (95% CI 31.91% to 39.18%).
  • Carrier status and polygenic score interacted significantly for female breast cancer and prostate cancer. In both, the polygenic score had a weaker effect in carriers than in noncarriers.
  • For several cancers, carriers with low polygenic scores had a lower estimated probability of cancer by age 75 than noncarriers with high scores.
  • Increased risks for stomach (HR 2.10, p = 0.03), esophagus (HR 2.07, p = 0.02) and uterine cancer (HR 1.69, p = 0.05) did not reach statistical significance after correction for multiple tests.
• The authors' conclusion: The authors concluded that BRCA2 pathogenic variants were linked to the classic HBOC cancers and six other cancer types. They also concluded that cancer-specific polygenic scores modify these risks and should be included in risk estimates for carriers.
• Limitations the authors state:
  • The number of BRCA2 carriers was limited, which reduced the study's power to detect associations with rare cancers; null results should be read with caution.
  • False positives are possible for the six newly linked cancers, because there were few prior reports and fewer than 50 patients with each cancer among carriers.
  • Results were mostly driven by people of European ancestry.
  • Some polygenic scores may be overfitted because UK Biobank participants helped develop them.
  • The prediction models were tested on the other half of the same population, which may also cause overfitting.
  • Family history was not included because it was limited in the UK Biobank.

Topics

Medical terms in this study, explained in our Lexicon: Ovarian Cancer, Cohort Study, Mesothelioma, Hazard Ratio, Genetic Counseling.

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