Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE)

Wang, Zhaoming; Liu, Qi; Wilson, Carmen L.; Easton, John; Mulder, Heather L.; Chang, Ti Cheng; Rusch, Michael; Edmonson, Michael N.; Rice, Stephen V.; Ehrhardt, Matthew J.; Howell, Rebecca M.; Kesserwan, Chimene; Wu, Gang; Nichols, Kim E.; Downing, James R.; Hudson, Melissa M.; Zhang, Jinghui; Yasui, Yutaka; Robison, Leslie L.

doi:10.1158/1078-0432.ccr-18-1775

Cited by 20 publications

(15 citation statements)

References 25 publications

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“…There is growing interest in leveraging knowledge of established meta-GWAS hits though PRS in specialized clinical populations such as childhood cancer survivors. 60 The suitability of translating this knowledge to such populations, however, depends on the generalizability of general population SNP associations to the clinical population of interest. We evaluated the generalizability of 1,376 SNP associations reported in 46 selected meta-GWAS for 12 anthropometric and cardiometabolic phenotypes in a large cohort of adult survivors of pediatric cancer in SJLIFE using genotypes from whole-genome sequencing and clinically ascertained phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Generalizability of “GWAS Hits” in Clinical Populations: Lessons from Childhood Cancer Survivors

Qin

Wang

et al. 2020

The American Journal of Human Genetics

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With mounting interest in translating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse clinical settings, evaluating their generalizability in target populations is crucial. Here, we consider long-term survivors of childhood cancers from the St. Jude Lifetime Cohort Study, and we show the limited generalizability of 1,376 robust SNP associations reported in the general population across 12 complex anthropometric and cardiometabolic phenotypes (n ¼ 2,231; observedto-expected replication ratio ¼ 0.70, p ¼ 6.2 3 10 À8 ). An examination of five comparable phenotypes in a second independent cohort of survivors from the Childhood Cancer Survivor Study corroborated the overall limited generalizability of meta-GWAS hits to survivors (n ¼ 4,212; observed-to-expected replication ratio ¼ 0.55, p ¼ 5.6 3 10 À15 ). Finally, in direct comparisons of survivor samples against independent equivalently powered general population samples from the UK Biobank, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score predictive performance in survivor samples for multiple phenotypes. As a possible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who had been exposed to cancer therapies that are associated with phenotype risk. Examination of complementary DNA methylation data in a subset of survivors revealed that treatment-related methylation patterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivors.

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Section: Discussionmentioning

confidence: 99%

Generalizability of “GWAS Hits” in Clinical Populations: Lessons from Childhood Cancer Survivors

Qin

Wang

et al. 2020

The American Journal of Human Genetics

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“…We recently reported that combinations of rare and common genetic variants associated with breast cancer in the general population increase subsequent breast cancer risk in childhood cancer survivors. 27 Future investigations are needed to understand anthracyclineassociated risk, not only in the context of variants associated with breast cancer, but other factors such as anthracycline metabolism, as well. Collectively, these studies suggest that women exposed to higher doses of anthracyclines are at substantially increased risk for breast cancer, yet to date, survivorship guidelines only address women who received chest radiation, likely missing a subgroup for whom routine surveillance would be equally beneficial.…”

Section: Discussionmentioning

confidence: 99%

Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE)

Ehrhardt

Howell

Hale

et al. 2019

JCO

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PURPOSE Anthracycline-associated risk for subsequent breast cancer in childhood cancer survivors is hypothesized to be mediated by TP53 mutation-related gene-environment interactions. We characterized treatment/genetic risks and the impact of screening for breast cancer in the St Jude Lifetime Cohort. PATIENTS AND METHODS Female participants underwent risk-based assessments, prior health event validation, chest radiation dosimetry, and whole genome sequencing. Breast biopsy reports were reviewed. A subgroup (n = 139) underwent both breast magnetic resonance imaging and mammography. Multivariable regression was used to calculate hazard ratios (HRs) and 95% CIs. RESULTS Among 1,467 women, 56 developed 68 breast cancers at a median age 38.6 (range, 24.5 to 53.0) years. Cumulative incidences at age 35 years were 1% (no chest radiation) and 8% (≥ 10 Gy of chest radiation). In adjusted models, breast cancer was associated with 20 Gy or more of chest radiation versus none (HR, 7.6; 95% CI, 2.9 to 20.4), anthracycline exposure versus none (1 to 249 mg/m2: HR, 2.6; 95% CI, 1.1 to 6.2; ≥ 250 mg/m2: HR, 13.4, 95% CI, 5.5 to 32.5), and having a breast cancer predisposition gene mutation (HR, 23.0; 95% CI, 7.3 to 72.2). Anthracyclines 250 mg/m2 or greater remained significantly associated with increased risk of breast cancer in models excluding survivors with cancer predisposition gene mutations, chest radiation 10 Gy or greater, or both. Sensitivity/specificity were 53.8%/96.3% for mammography, 69.2%/91.4% for magnetic resonance imaging, and 85.8%/99.7% for dual imaging. Breast cancers detected by imaging and/or prophylactic mastectomy compared with physical findings were more likely to be in situ carcinomas, smaller, without lymph node involvement, and treated without chemotherapy. CONCLUSION Higher doses of anthracyclines are associated with increased risk of breast cancer independent of mutations in known cancer predisposition genes. Surveillance imaging identifies breast cancers less likely to require chemotherapy than those detected by physical findings.

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“…However, not all studies have weighted the breast cancer variants for their specific ethic group, and therefore findings may not be an accurate representation of breast cancer risk for their population [35]. An increased rate of contralateral breast cancer has also been reported for women with a PRS in the highest quartile of risk distribution [7,37,44].…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field

et al. 2020

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Polygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discussed.

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Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE)

Cited by 20 publications

References 25 publications

Generalizability of “GWAS Hits” in Clinical Populations: Lessons from Childhood Cancer Survivors

Generalizability of “GWAS Hits” in Clinical Populations: Lessons from Childhood Cancer Survivors

Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE)

Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field

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