ABSTRACT
PURPOSE: Trials demonstrating benefits of tamoxifen for women with ductal carcinoma in situ (DCIS) were published > 20 years ago; yet subsequent uptake of endocrine therapy was low. We estimated endocrine therapy initiation in women with DCIS between 2001 and 2018 in a community setting, reflecting more recent years of diagnosis than previous studies. METHODS: This retrospective cohort included adult females ≥ 20 years diagnosed with first primary DCIS between 2001 and 2018, followed through 2019, and enrolled in one of three U.S. integrated healthcare systems. We collected data on endocrine therapy dispensings (tamoxifen, aromatase inhibitors [AIs]) from electronic pharmacy records within 12 months after DCIS diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated endocrine therapy initiation rates over time and by patient, tumor (including estrogen receptor [ER] status), and treatment characteristics. RESULTS: Among 2020 women with DCIS, 587 (29%) initiated endocrine therapy within 12 months after diagnosis (36% among 1208 women with ER-positive DCIS). Among women who used endocrine therapy, 506 (86%) initiated tamoxifen and 81 (14%) initiated AIs. Age-adjusted endocrine therapy initiation declined from 34 to 21% between 2001 and 2017; between 2015 and 2018, AI use increased from 8 to 35%. Women less likely to initiate endocrine therapy were ER-negative or had borderline/unknown or no ER test results, ≥ 65 years at diagnosis, Black, and received no radiotherapy. CONCLUSION: One-third of women diagnosed with DCIS initiated endocrine therapy, and use decreased over time. Understanding why women eligible for endocrine therapy do not initiate is important to maximizing disease-free survival following DCIS diagnosis.
ABSTRACT
BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Genome-Wide Association Study , Jews/genetics , Israel/epidemiology , Genetic Predisposition to Disease , Risk Factors , Multifactorial Inheritance/genetics , Transcription FactorsABSTRACT
BACKGROUND: Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking. METHODS: We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis. RESULTS: Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62-1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37-1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65-6.33), soft tissue (SIR = 3.32, 95%CI = 2.51-4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82-3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18-3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89-5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31-1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01-1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17-4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78-0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01-8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38-0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers. CONCLUSIONS: Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.
Subject(s)
Breast Neoplasms , Cancer Survivors , Myelodysplastic Syndromes , Neoplasms, Second Primary , Humans , Female , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Breast Neoplasms/therapy , Risk Factors , Incidence , Myelodysplastic Syndromes/complicationsABSTRACT
BACKGROUND: Prenatal exposure to diethylstilbestrol (DES) is associated with several adverse health outcomes. Animal studies have shown associations between prenatal DES exposure and DNA methylation. OBJECTIVE: The aim of this study was to explore blood DNA methylation in women exposed and unexposed to DES in utero. METHODS: Sixty women (40 exposed and 20 unexposed) in the National Cancer Institute's Combined DES Cohort Study and 199 women (99 exposed and 100 unexposed women) in the Sister Study Cohort were included in this analysis. Within each study, robust linear regression models were used to assess associations between DES exposure and blood DNA methylation. Study-specific associations were combined using fixed-effect meta-analysis with inverse variance weights. Our analysis focused on CpG sites located within nine candidate genes identified in animal models. We further explored whether in utero DES exposure was associated with age acceleration. RESULTS: Blood DNA methylation levels at 10 CpG sites in six of the nine candidate genes were statistically significantly associated with prenatal DES exposure (P < 0.05) in this meta-analysis. Genes included EGF, EMB, EGFR, WNT11, FOS, and TGFB1, which are related to cell proliferation and differentiation. The most statistically significant CpG site was cg19830739 in gene EGF, and it was associated with lower methylation levels in women prenatally exposed to DES compared with those not exposed (P < 0.0001; false discovery rate<0.05). The association between prenatal DES exposure in utero and age acceleration was not statistically significant (P = 0.07 for meta-analyzed results). CONCLUSIONS: There are few opportunities to investigate the effects of prenatal DES exposure. These findings suggest that in utero DES exposure may be associated with differential blood DNA methylation levels, which could mediate the increased risk of several adverse health outcomes observed in exposed women. Our findings need further evaluation using larger data sets.
Subject(s)
Diethylstilbestrol , Prenatal Exposure Delayed Effects , Pregnancy , Humans , Female , Diethylstilbestrol/toxicity , Cohort Studies , DNA Methylation , Prenatal Exposure Delayed Effects/chemically induced , Epidermal Growth FactorABSTRACT
BACKGROUND: Soft tissue sarcoma is a rare but serious side-effect of radiotherapy to treat breast cancer, and rates are increasing in the USA. We evaluated potential co-factors in two complimentary cohorts of US breast cancer survivors. METHODS: In this retrospective cohort study, we sourced data from the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort, both in the USA. The KP cohort included 15 940 women diagnosed with breast cancer from Jan 1, 1990, to Dec 31, 2016, in KP Colorado, KP Northwest (which serves Oregon and Southwest Washington state), or KP Washington, with detailed treatment data and comorbidities (including hypertension and diabetes at or before breast cancer diagnosis) from electronic medical records. The SEER cohort included 457 300 women diagnosed with breast cancer from Jan 1, 1992, to Dec 31, 2016, within the 13 SEER registries across the USA, with initial treatment data (yes vs no or unknown). Eligibility criteria in both cohorts were female breast cancer survivors (stage I-III) aged 20-84 years at diagnosis who had breast cancer surgery, and had survived at least 1 year after breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed at least 1 year after breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models. FINDINGS: In the KP cohort, median follow-up was 9·3 years (IQR 5·7-13·9) and 19 (0·1%) of 15 940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes). Most (94·7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (relative risk [RR] 8·1 [95% CI 1·1-60·4]; p=0·0052), but there was no association with prescribed dose, fractionation, or boost. The RR of angiosarcoma after anthracyclines was 3·6 (95% CI 1·0-13·3; p=0·058). Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7·7 [95% CI 1·2-150·8]; p=0·026). History of hypertension (RR 4·8 [95% CI 1·3-17·6]; p=0·017) and diabetes (5·3 [1·4-20·8]; p=0·036) were each associated with around a five-times increased risk of angiosarcoma. In the SEER cohort, 430 (0·1%) of 457 300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8·3 years (IQR 4·3-13·9). Most (77·9%; 335 of 430) cases occurred after radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR 3·0 [95% CI 2·4-3·8]; p<0·0001) and, for angiosarcomas, the RR for breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1·9 (1·1-3·3; p=0·012). By 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0·21% (95% CI 0·12-0·34) in the KP cohort and 0·15% (95% CI 0·13-0·17) in SEER. INTERPRETATION: Radiotherapy was the strongest risk factor for thoracic soft tissue sarcoma in both cohorts. This finding, along with the novel findings for diabetes and hypertension as potential risk factors for angiosarcomas, warrant further investigation as potential targets for prevention strategies and increased surveillance. FUNDING: US National Cancer Institute and National Institutes of Health.
Subject(s)
Breast Neoplasms , Cancer Survivors , Hemangiosarcoma , Hypertension , Neoplasms, Second Primary , Sarcoma , Soft Tissue Neoplasms , Female , Humans , Male , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Breast Neoplasms/complications , Hemangiosarcoma/epidemiology , Hemangiosarcoma/etiology , Hemangiosarcoma/therapy , Retrospective Studies , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Mastectomy/adverse effects , Sarcoma/epidemiology , Sarcoma/therapy , Soft Tissue Neoplasms/surgery , Cohort Studies , Risk Factors , Hypertension/epidemiology , Hypertension/complicationsABSTRACT
BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.
Subject(s)
Breast Neoplasms , Aging/genetics , Breast Neoplasms/etiology , Breast Neoplasms/genetics , DNA Methylation , Epigenesis, Genetic , Female , Humans , Life Style , Prospective Studies , Risk FactorsABSTRACT
PURPOSE: This retrospective cohort study examined patterns of endocrine therapy initiation over time and by demographic, tumor, and treatment characteristics. METHODS: We included 7777 women from three U.S. integrated healthcare systems diagnosed with incident stage I-III hormone receptor-positive breast cancer between 2001 and 2016. We extracted endocrine therapy from pharmacy dispensings, defining initiation as dispensings within 12 months of diagnosis. Demographic, tumor, and treatment characteristics were collected from electronic health records. Using generalized linear models with a log link and Poisson distribution, we estimated initiation of any endocrine therapy, tamoxifen, and aromatase inhibitors (AI) over time with relative risks (RR) and 95% confidence intervals (CI) adjusted for age, tumor characteristics, diagnosis year, other treatment, and study site. RESULTS: Among women aged 20+ (mean 62 years), 6329 (81.4%) initiated any endocrine therapy, and 1448 (18.6%) did not initiate endocrine therapy. Tamoxifen initiation declined from 67 to 15% between 2001 and 2016. AI initiation increased from 6 to 69% between 2001 and 2016 in women aged ≥ 55 years. The proportion of women who did not initiate endocrine therapy decreased from 19 to 12% between 2002 and 2014 then increased to 17% by 2016. After adjustment, women least likely to initiate endocrine therapy were older (RR = 0.81, 95% CI 0.77-0.85 for age 75+ vs. 55-64), Black (RR = 0.93, 95% CI 0.87-1.00 vs. white), and had stage I disease (RR = 0.88, 95% CI 0.85-0.91 vs. stage III). CONCLUSIONS: Despite an increase in AI use over time, at least one in six eligible women did not initiate endocrine therapy, highlighting opportunities for improving endocrine therapy uptake in breast cancer survivors.
Subject(s)
Breast Neoplasms , Antineoplastic Agents, Hormonal/therapeutic use , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Female , Humans , Retrospective Studies , Tamoxifen/therapeutic useABSTRACT
PURPOSE: Estrogen receptor (ER) + /progesterone receptor (PR) - or ER-/PR + breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER + /PR-, ER-/PR + , ER + /PR + , ER-/PR-) subgroups and breast cancer-specific mortality within a general community setting in the US. METHODS: A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990 and 2016 within US integrated healthcare systems (median follow-up = 7 years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy). RESULTS: Breast cancer-specific mortality was higher for those with ER + /PR- (n = 1,233) compared with ER + /PR + tumors (n = 8,439) before (HR = 1.43; 95% CI = 1.17-1.75) and after treatment adjustment (HR = 1.58; 95% CI = 1.27-1.97). ER + /PR- breast cancer-specific mortality remained higher than ER + /PR + tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER-/PR + (n = 161) compared with ER + /PR + tumors. CONCLUSION: Our findings suggest that ER + /PR- tumors may have worse breast cancer-specific mortality than ER + /PR + tumors in a community setting.
Subject(s)
Breast Neoplasms , Delivery of Health Care, Integrated , Breast Neoplasms/pathology , Female , Hormones/therapeutic use , Humans , Prognosis , Receptor, ErbB-2 , Receptors, Estrogen , Receptors, Progesterone , Retrospective StudiesABSTRACT
BACKGROUND: Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. METHODS: Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. RESULTS: Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p < 0.001) and with local percent mammographic density volume at both the biopsy target (p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p < 0.05). CONCLUSIONS: Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.
Subject(s)
Breast Density , Breast/metabolism , Breast/pathology , Collagen/metabolism , Adult , Aged , Breast/diagnostic imaging , Breast Diseases/diagnostic imaging , Breast Diseases/metabolism , Breast Diseases/pathology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Image-Guided Biopsy , Mammography , Microscopy , Middle Aged , Stromal Cells/metabolism , Stromal Cells/pathologyABSTRACT
PURPOSE: The role of established breast cancer risk factors and clinical characteristics of the first breast cancer in the development of contralateral breast cancer (CBC) among postmenopausal women is unclear. METHODS: We identified 10,934 postmenopausal women diagnosed with a first primary breast cancer between 1995 and 2011 in the NIH-AARP Diet and Health Study. CBC was defined as a second primary breast cancer diagnosed in the contralateral breast ≥ 3 months after the first breast cancer. Exposures included pre-diagnosis risk factors (lifestyle, reproductive, family history) and clinical characteristics of the first breast cancer. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median follow-up of 6.8 years, 436 women developed CBC. We observed an increasing trend in CBC risk by age (p-trend = 0.002) and decreasing trend by year of diagnosis (p-trend = 0.001) of the first breast cancer. Additional risk factor associations were most pronounced for endocrine therapy (HR 0.68, 95% CI 0.53-0.87) and family history of breast cancer (HR 1.38, 95% CI 1.06-1.80, restricted to invasive first breast cancer). No associations were found for lifestyle (body mass index, physical activity, smoking, alcohol) or reproductive factors (age at menarche, parity, age at first birth, age at menopause). CONCLUSIONS: This study suggests that clinical characteristics of the first breast cancer and family history of breast cancer, but not pre-diagnosis lifestyle and reproductive factors, are strongly associated with CBC risk among postmenopausal women. Future studies are needed to understand how these factors contribute to CBC etiology and to identify further opportunities for prevention.
Subject(s)
Breast Neoplasms/etiology , Cancer Survivors , Neoplasms, Second Primary/etiology , Postmenopause , Aged , Body Mass Index , Diet , Female , Humans , Life Style , Menarche , Menopause , Middle Aged , Proportional Hazards Models , Reproductive History , Risk FactorsABSTRACT
Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014-2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low-dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number changes, structural variants, genomic insertions and deletions, methylation profiles, and telomere length. Genomic alterations are being examined in relation to parental gonadal dose, reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examination of parental origin, duration, and timing of exposure in relation to conception. Here we describe the study methodology and recruitment results and provide descriptive information on the first 150 families (mother-father-child(ren)) enrolled.
Subject(s)
Chernobyl Nuclear Accident , Germ-Line Mutation , Maternal Exposure/adverse effects , Paternal Exposure/adverse effects , Radiation Dosage , Adult , Female , Follow-Up Studies , Humans , Male , Young AdultABSTRACT
BACKGROUND: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. METHODS: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. RESULTS: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). CONCLUSIONS: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
Subject(s)
Breast Neoplasms/genetics , Circulating Tumor DNA , DNA Methylation , DNA, Neoplasm , Epigenesis, Genetic , Breast Neoplasms/blood , Case-Control Studies , CpG Islands , Female , Gene Expression Profiling , Humans , Middle Aged , Odds Ratio , Prospective Studies , Risk Assessment , Risk FactorsABSTRACT
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from Subject(s)
Biomarkers, Tumor/genetics
, DNA Methylation
, Oligonucleotide Array Sequence Analysis/methods
, Uterine Cervical Dysplasia/genetics
, Uterine Cervical Neoplasms/genetics
, Adult
, Aged
, Area Under Curve
, CpG Islands
, Early Detection of Cancer
, Female
, Human papillomavirus 16/isolation & purification
, Humans
, Middle Aged
, Papillomavirus Infections/diagnosis
, Papillomavirus Infections/genetics
, Prospective Studies
, Sequence Analysis, DNA/methods
, Uterine Cervical Neoplasms/virology
, Young Adult
, Uterine Cervical Dysplasia/virology
ABSTRACT
Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.
Subject(s)
Breast Neoplasms/genetics , Genes, Neoplasm , Mammary Glands, Human/ultrastructure , Polymorphism, Single Nucleotide , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Alleles , Biopsy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Case-Control Studies , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Humans , Menopause , Middle Aged , Risk , Surveys and Questionnaires , Young AdultABSTRACT
Persistent infection with carcinogenic human papillomaviruses (HPV) causes the majority of anogenital cancers and a subset of head and neck cancers. The HPV genome is frequently found integrated into the host genome of invasive cancers. The mechanisms of how it may promote disease progression are not well understood. Thoroughly characterizing integration events can provide insights into HPV carcinogenesis. Individual studies have reported limited number of integration sites in cell lines and human samples. We performed a systematic review of published integration sites in HPV-related cancers and conducted a pooled analysis to formally test for integration hotspots and genomic features enriched in integration events using data from the Encyclopedia of DNA Elements (ENCODE). Over 1,500 integration sites were reported in the literature, of which 90.8% (N = 1,407) were in human tissues. We found 10 cytobands enriched for integration events, three previously reported ones (3q28, 8q24.21 and 13q22.1) and seven additional ones (2q22.3, 3p14.2, 8q24.22, 14q24.1, 17p11.1, 17q23.1 and 17q23.2). Cervical infections with HPV18 were more likely to have breakpoints in 8q24.21 (p = 7.68 × 10(-4) ) than those with HPV16. Overall, integration sites were more likely to be in gene regions than expected by chance (p = 6.93 × 10(-9) ). They were also significantly closer to CpG regions, fragile sites, transcriptionally active regions and enhancers. Few integration events occurred within 50 Kb of known cervical cancer driver genes. This suggests that HPV integrates in accessible regions of the genome, preferentially genes and enhancers, which may affect the expression of target genes.
Subject(s)
Alphapapillomavirus/physiology , Head and Neck Neoplasms/virology , Papillomavirus Infections/genetics , Urogenital Neoplasms/virology , Virus Integration , Alphapapillomavirus/genetics , Chromosome Breakpoints , Chromosome Fragile Sites , CpG Islands , Female , Genome, Human , Head and Neck Neoplasms/genetics , Humans , Male , Proto-Oncogenes , Urogenital Neoplasms/geneticsABSTRACT
Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.
Subject(s)
Breast Neoplasms/etiology , Mammary Glands, Human/anatomy & histology , Menarche/genetics , Menopause , Polymorphism, Single Nucleotide , Adult , Age Factors , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Mammary Glands, Human/pathology , Middle AgedABSTRACT
BACKGROUND: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis. METHODS: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses). RESULTS: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non-proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95% CI: 1.47, 4.42). CONCLUSIONS: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Leukocytes/metabolism , Mammary Glands, Human/abnormalities , Telomere/genetics , Adult , Aged , Breast Density , Cross-Sectional Studies , Female , Humans , Image-Guided Biopsy , Middle Aged , Neoplasm Staging , Risk FactorsABSTRACT
Genital infection with the oncogenic human papillomavirus is the necessary cause of cervical cancer and of a large fraction of vulvar cancers. The toll-like receptor and the nuclear factor κB (NF-κB) signaling pathways have been implicated in inflammation, autoimmune disease and cancer, but whether common nucleotide variation in these pathways is associated with the risk of cervical and vulvar cancers has received little study. Using data from a population-based case-control study of cervical and vulvar cancers, we genotyped 205 single nucleotide polymorphisms (SNPs) in and around 32 candidate gene regions within these pathways. Gene-based analyses were used to estimate the associations between individual gene regions and the risk of cervical and vulvar cancers. Odds ratio (OR) and 95% confidence intervals (CI) were calculated to assess the risk of cervical and vulvar cancers for each SNP. p-Values were adjusted for multiple testing. A total of 876 cervical cancer cases, 517 vulvar cancer cases and 1,100 controls were included in the analysis. The TNF region was significantly associated with the risks of cervical cancer (gene-based p-value: 2.0 × 10(-4) ) and vulvar cancer (gene-based p-value: 1.0 × 10(-4) ). The rare allele (A) of SNP rs2239704 in the 5' UTR of the LTA gene was significantly associated with increased risks of cervical cancer (OR=1.31, 95% CI: 1.15-1.50; adjusted p-value: 0.013) and vulvar cancer (OR=1.51, 95% CI: 1.30-1.75; adjusted p-value: 1.9 × 10(-5) ). These findings add to the evidence of the importance of the immune system in the etiology of cervical and vulvar cancers.
Subject(s)
5' Untranslated Regions/genetics , Lymphotoxin-alpha/genetics , NF-kappa B/genetics , Polymorphism, Single Nucleotide/genetics , Toll-Like Receptors/genetics , Uterine Cervical Neoplasms/genetics , Vulvar Neoplasms/genetics , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adolescent , Adult , Aged , Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/epidemiology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Female , Follow-Up Studies , Genetic Predisposition to Disease , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Risk Factors , Signal Transduction , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/pathology , Vulvar Neoplasms/epidemiology , Vulvar Neoplasms/pathology , Washington/epidemiology , Young AdultABSTRACT
Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which are qualitative and do not account for noncancerous elements within the tumor microenvironment. Here we present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast tumor microenvironment morphology. HiPS uses deep learning to accurately map cellular and tissue structures to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study-II and validated using data from three independent cohorts, including the Prostate, Lung, Colorectal, and Ovarian Cancer trial, Cancer Prevention Study-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists in predicting survival outcomes, independent of tumor-node-metastasis stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve patient prognosis.