Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores
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 (...
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Wiley
2025-06-01
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| Online Access: | https://doi.org/10.1002/cam4.70990 |
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| author | Brendan Prassas Zhuqing Shi Huy Tran Jun Wei Chi‐Hsiung Wang Andrew S. Rifkin Annabelle Ashworth S. Lilly Zheng Ashley J. Mulford Alan R. Sanders Catherine E. Pesce Brian T. Helfand Henry M. Dunnenberger David Duggan Peter J. Hulick Allison DePersia Jianfeng Xu |
| author_facet | Brendan Prassas Zhuqing Shi Huy Tran Jun Wei Chi‐Hsiung Wang Andrew S. Rifkin Annabelle Ashworth S. Lilly Zheng Ashley J. Mulford Alan R. Sanders Catherine E. Pesce Brian T. Helfand Henry M. Dunnenberger David Duggan Peter J. Hulick Allison DePersia Jianfeng Xu |
| author_sort | Brendan Prassas |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc18f0736506494da86c4749d05df8d0 |
| institution | DOAJ |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj-art-bc18f0736506494da86c4749d05df8d02025-08-20T03:21:19ZengWileyCancer Medicine2045-76342025-06-011411n/an/a10.1002/cam4.70990Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic ScoresBrendan Prassas0Zhuqing Shi1Huy Tran2Jun Wei3Chi‐Hsiung Wang4Andrew S. Rifkin5Annabelle Ashworth6S. Lilly Zheng7Ashley J. Mulford8Alan R. Sanders9Catherine E. Pesce10Brian T. Helfand11Henry M. Dunnenberger12David Duggan13Peter J. Hulick14Allison DePersia15Jianfeng Xu16Program for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAGenomic Health Initiative NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAGenomic Health Initiative NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USADepartment of Surgery NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USANeaman Center for Personalized Medicine NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USATranslational Genomics Research Institute, Part of City of Hope Phoenix Arizona USANeaman Center for Personalized Medicine NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USANeaman Center for Personalized Medicine NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAProgram for Genomic Translational Research NorthShore University HealthSystem (Endeavor Health) Evanston Illinois USAABSTRACT 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.https://doi.org/10.1002/cam4.70990BRCA2breast cancer (female and male)hereditary breast and ovarian cancer syndrome (HBOC)liver cancerlung canceroral cancer |
| spellingShingle | Brendan Prassas Zhuqing Shi Huy Tran Jun Wei Chi‐Hsiung Wang Andrew S. Rifkin Annabelle Ashworth S. Lilly Zheng Ashley J. Mulford Alan R. Sanders Catherine E. Pesce Brian T. Helfand Henry M. Dunnenberger David Duggan Peter J. Hulick Allison DePersia Jianfeng Xu Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores Cancer Medicine BRCA2 breast cancer (female and male) hereditary breast and ovarian cancer syndrome (HBOC) liver cancer lung cancer oral cancer |
| title | Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores |
| title_full | Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores |
| title_fullStr | Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores |
| title_full_unstemmed | Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores |
| title_short | Estimating Cancer Penetrance in Carriers of BRCA2 Pathogenic Variants Using Cancer‐Specific Polygenic Scores |
| title_sort | estimating cancer penetrance in carriers of brca2 pathogenic variants using cancer specific polygenic scores |
| topic | BRCA2 breast cancer (female and male) hereditary breast and ovarian cancer syndrome (HBOC) liver cancer lung cancer oral cancer |
| url | https://doi.org/10.1002/cam4.70990 |
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