Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study

Abstract P6-09-04: Benign breast disease and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC)

Abstract Background: Benign breast disease (BBD) is one of the strongest risk factors for breast cancer but it is unclear whether the strength of the association with BBD and breast cancers varies by breast cancer family history. Few studies of BBD enrich specifically for putative genetic factors by over-sampling based on family history let alone evaluate potential interactions with measures of underlying familial risk. The aim of this study was to evaluate how risk associated with BBD is modified by underlying familial risk so as to guide clinical management and risk assessment of women with BBD. Methods: Using a prospective family study cohort of 17,154 women unaffected with breast cancer at baseline and followed by questionnaire at regular intervals, we examined the association between BBD and breast cancer risk using Cox Proportional Hazards models. We classified women as having BBD if they reported at baseline having been told by a doctor that they had BBD, such as a non-cancerous cyst or breast lump. We did not have information on histologic sub-type. We confirmed self-reported diagnosis of BBD with pathology reports in a subset of the New York cohort and found high agreement between self-reported and pathologically confirmed BBD (93.5%). We assessed multiplicative and additive interactions with underlying familial risk profile (FRP) defined as either fixed-time horizon of 1-year, or total lifetime risk, estimated from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. Results: During 176,756 person-years of follow-up (mean 10.2, maximum 23.7 years), we observed 968 incident breast cancers cases with an average age at diagnosis of 55.8 years and average age at enrollment into the cohort of 46.8 years. At baseline, 4,704 (27%) women reported having a previous diagnosis of BBD. Compared to women with no history of BBD, breast cancer risk was increased in women of all ages (HR: 1.37, 95% CI: 1.19,1.56), and in women up to age 45 years (using attained age models) (HR: 1.40, 95% CI: 1.01,1.93). In terms of recency of BBD, we found that the increased risk associated with BBD remained 21 years or more after the initial BBD diagnosis (HR: 1.37, 95% CI: 1.11, 1.68). We found no evidence for multiplicative interactions with FRP, which implies that the increase in absolute risk associated with BBD depends on a woman's FRP (Table 1). Conclusions: Women with a history of BBD have an increased risk of breast cancer that multiplies their underlying familial risk (FRP). These results could prove to be valuable for risk counseling and clinical management. Table 1: Cumulative Incidence of Breast Cancer to age 45, 55, and 65 by BBD and underlying FRP as measured by 10-year BOADICEA score.AgeNo BBD, &amp;lt;3.4 %BBD, &amp;lt;3.4%No BBD, ≥3.4%BBD, ≥3.4%454.6 (3.8, 5.6)6.1(4.7, 8.0)12.1 (10.2, 14.5)16.1 (13.1, 19.7)557.4 (6.3, 8.7)9.8 (7.5, 12.8)19.1 (16.6, 22.0)25.0 (21.7, 28.9)659.7 (8.2, 11.5)12.8 (9.9, 16.5)24.5 (21.8, 27.6)31.8 (28.3, 35.7) Citation Format: Zeinomar N, Phillips KA, Liao Y, MacInnis RJ, Dite GS, Daly MB, John EM, Andrulis IL, Buys SS, Hopper JL, Terry MB. Benign breast disease and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-04.</jats:p

Abstract P6-09-01: Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC)

Abstract Background: Whether risk-reducing salpingo oophorectomy (RRSO) reduces breast cancer risk in addition to reducing ovarian cancer risk is controversial with some arguing that the previous evidence of a reduction in breast cancer risk from RRSO was due to bias. Evidence from independent prospective cohorts of high-risk women is needed to resolve this controversy. Methods: Using a prospective family study cohort of 17,810 women unaffected with breast cancer at baseline, we examined the association between RRSO and breast cancer risk using Cox Proportional Hazards models. We compared results estimating RRSO as a non-time-dependent variable to results treating RRSO as a time-dependent variable, because failing to account for the time-varying nature of a covariate person- time prior to RRSO, should it exist, will incorrectly attribute the cancer-free person-time to RRSO. We separately examined the association with RRSO in BRCA1 and BRCA2 mutation carriers and non-carriers, and further performed gene-stratified analyses in women with BRCA1 and BRCA2 only. We also assessed multiplicative interactions with underlying familial risk profile (FRP), defined as total lifetime risk estimated from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. Results: During a median 10.7 years of follow-up (maximum 23.7 years), we observed 1,040 incident cases of breast cancer with an average age at diagnosis of 55.8 years and average age at enrollment into the cohort of 46.8 years. A total of 2434 (14%) women reported at baseline having a RRSO. We observed decreased risk of breast cancer associated with RRSO for both BRCA1(N= 650) and BRCA2(N=557) mutation carriers when RRSO was treated as a fixed covariate (HR= 0.60, 95% CI=0.40-0.92 and HR= 0.40, 95%CI = 0.23-0.69, respectively). In contrast, when we treated RRSO as a time-varying covariate, for both BRCA1 and BRCA2 carriers, we no longer observed a decreased risk for BRCA1 and BRCA2 carriers (HR= 1.67, 95% CI=1.05-2.67 and HR= 0.97, 95%CI = 0.53-1.80, respectively). There was no association between RRSO and breast cancer risk for non-carriers (N=16,603), whether we treated RRSO as a fixed or time varying covariate (HR= 0.88, 95% CI=0.72-1.08 and HR= 1.06, 95%CI = 0.85-1.30, respectively). Conclusions: Our findings provide an independent replication that the reduced risk of breast cancer previously observed in BRCA1 and BRCA2 mutation carrier women may be from bias in counting person-time. Clinical management of high-risk women should counsel based on the reduced risk of ovarian cancer from RRSO, but not breast cancer. Citation Format: Terry MB, Phillips KA, Daly MB, Andrulis IL, Liao Y, Ma X, Zeinomar N, MacInnis RJ, Dite GS, John EM, Buys SS, Hopper JL. Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-01.</jats:p

Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk

There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17 917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7 years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR = 0.68, 95% CI = 0.32 to 1.47, HR = 0.94, 95% CI = 0.70 to 1.26, and HR = 1.10, 95% CI = 0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk

Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort

Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14-1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11-1.65), 1.26 (95% CI: 1.00-1.60), and 1.40 (95% CI: 1.01-1.93), for categories of full-lifetime BOADICEA score <20%, 20 to <35%, ≥35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04-2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78-2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13-1.53) (pinteraction  = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk

Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk

Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history (N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68-0.93). The association was not modified by familial risk or BRCA mutation status (P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk. SIGNIFICANCE: These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility.See related commentary by Niehoff et al., p. 23

Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk

BACKGROUND: Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs). METHODS: We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided. RESULTS: We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events. CONCLUSION: Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs