Somatic genetic aberrations in benign breast disease and the risk of subsequent breast cancer.
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ABSTRACT:
SUBMITTER: Zeng Z
PROVIDER: S-EPMC7293275 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Somatic genetic aberrations in benign breast disease and the risk of subsequent breast cancer.
Zeng Zexian Z Vo Andy A Li Xiaoyu X Shidfar Ali A Saldana Paulette P Blanco Luis L Xuei Xiaoling X Luo Yuan Y Khan Seema A SA Clare Susan E SE
NPJ breast cancer 20200612
It is largely unknown how the development of breast cancer (BC) is transduced by somatic genetic alterations in the benign breast. Since benign breast disease is an established risk factor for BC, we established a case-control study of women with a history of benign breast biopsy (BBB). Cases developed BC at least one year after BBB and controls did not develop BC over an average of 17 years following BBB. 135 cases were matched to 69 controls by age and type of benign change: non-proliferative ...[more]
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Project description:BACKGROUND:Insights into the molecular pathogenesis of breast cancer might come from molecular analysis of tissue from early stages of the disease. METHODS:We conducted a case-control study nested in a cohort of women who had biopsy-confirmed benign breast disease (BBD) diagnosed between 1971 and 2006 at Kaiser Permanente Northwest and who were followed to mid-2015 to ascertain subsequent invasive breast cancer (IBC); cases (n = 218) were women with BBD who developed subsequent IBC and controls, individually matched (1:1) to cases, were women with BBD who did not develop IBC in the same follow-up interval as that for the corresponding case. Targeted sequence capture and sequencing were performed for 83 genes of importance in breast cancer. RESULTS:There were no significant case-control differences in mutation burden overall, for non-silent mutations, for individual genes, or with respect either to the nature of the gene mutations or to mutational enrichment at the pathway level. For seven subjects with DNA from the BBD and ipsilateral IBC, virtually no mutations were shared. CONCLUSIONS:This study, the first to use a targeted multi-gene sequencing approach on early breast cancer precursor lesions to investigate the genomic basis of the disease, showed that somatic mutations detected in BBD tissue were not associated with breast cancer risk.
| S-EPMC6008400 | biostudies-literature
Project description:BackgroundBenign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis and how these relate to risk of incident BC.MethodsA subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC, and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two types of burden tests and adjusted for clinical and technical covariates.ResultsAfter filtering, the variant frequency of SNPs in our sample was highly consistent with population allele frequencies reported in 1 KG/ExAC (0.986, p < 1e-16). The top ten genes found to be nominally associated with later cancer status by four of 12 association methods(p < 0.05) were MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1, although these were not statistically significant in permutation testing. However, all 10 gene-level associations had OR < 1 with lower mutation burden in controls compared to cases, which was marginally statistically significant in permutation testing (p = 0.04). Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p < 0.001).ConclusionsSomatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development.
| S-EPMC8278587 | biostudies-literature
Project description:Benign breast disease (BBD) is an established risk factor for breast cancer among Caucasian women but less is known about BBD in African American women. As African American women suffer from disproportionate mortality due to breast cancer, special focus on pathologic characteristics that may influence disease risk is warranted. Benign breast biopsies from African American women were identified by the University Pathology Group (Detroit, MI). African American women of ages 20 to 84 years, who underwent a breast biopsy from 1997 to 2000, were eligible for the study. Subsequent breast cancers were identified through a linkage with the Detroit Surveillance Epidemiology and End Results (SEER) program. The first biopsy was reviewed by the pathologist, and lesions were classified following Dupont and Page criteria along with involution and other histologic features. Logistic regression was used to estimate the risk of developing a subsequent breast cancer with the histologic characteristics of BBD. A total of 1,406 BBD biopsies from African American women were included in this study with a median follow-up of 10.1 years. The majority (68%) showed nonproliferative disease, 29% had proliferative disease without atypia, and 3% had proliferative disease with atypia. Subsequent incident breast cancers occurred in 55 women (3.9%). Women whose biopsies showed proliferative disease with atypia were more than three-fold more likely to develop breast cancer as compared with women who had nonproliferative disease [relative risk (RR) 3.29, 95% confidence interval (CI) 1.21-8.93]. Better characterization of the risk of breast cancer among women with BBD, considering both ethnicity and detailed molecular findings, can lead to better surveillance, earlier diagnosis, and potentially improved survival.
| S-EPMC3518609 | biostudies-literature
Project description:New biomarkers of risk may improve breast cancer (BC) risk prediction. We developed a computational pathology method to segment benign breast disease (BBD) whole slide images into epithelium, fibrous stroma, and fat. We applied our method to the BBD BC nested case-control study within the Nurses' Health Studies to assess whether computer-derived tissue composition or a morphometric signature was associated with subsequent risk of BC. Tissue segmentation and nuclei detection deep-learning networks were established and applied to 3795 whole slide images from 293 cases who developed BC and 1132 controls who did not. Percentages of each tissue region were calculated, and 615 morphometric features were extracted. Elastic net regression was used to create a BC morphometric signature. Associations between BC risk factors and age-adjusted tissue composition among controls were assessed using analysis of covariance. Unconditional logistic regression, adjusting for the matching factors, BBD histological subtypes, parity, menopausal status, and body mass index evaluated the relationship between tissue composition and BC risk. All statistical tests were 2-sided. Among controls, direction of associations between BBD subtypes, parity, and number of births with breast composition varied by tissue region; select regions were associated with childhood body size, body mass index, age of menarche, and menopausal status (all P < .05). A higher proportion of epithelial tissue was associated with increased BC risk (odds ratio = 1.39, 95% confidence interval = 0.91 to 2.14, for highest vs lowest quartiles, Ptrend = .047). No morphometric signature was associated with BC. The amount of epithelial tissue may be incorporated into risk assessment models to improve BC risk prediction.
| S-EPMC7898083 | biostudies-literature
Project description:Background: Fibrocystic changes are associated with an increased risk of breast cancer. Genetic alterations have been found in fibrocystic changes with or without epithelial changes, suggesting that critical oncogenic events are occurring at an early stage. Methods: We investigated a unique collective of 17 breast cancer patients who, prior to the diagnosis of invasive breast cancer, underwent open surgical biopsy showing fibrocystic changes of the breast. The time span between biopsy for fibrocystic changes and invasive carcinoma ranged from 1 to 11 years (average 5.3 years). Ten (58.8%) of the patients had an ipsilateral invasive carcinoma, and 7 (41.2%) of the patients developed an invasive carcinoma of the contralateral breast. Massive parallel sequencing targeting genes frequently mutated in breast cancer was performed on the fibrocystic breast tissue as well as the ensuing cancer tissue. Results: In 9 cases, somatic mutations were found in the tumor tissue, the most prevalent being PIK3CA mutations (n = 4), followed by TP53 mutations (n = 2). None of these mutations were present in the previously removed mastopathy tissue. In one of the cases, an ERBB3 E928G mutation was present in the mastopathy as well as in the tumor tissue, with the variant allele frequency in the mastopathy being <0.1%. In two patients, we found two mutations (MAP3K1 L380fs and PIK3CA I391M, respectively) present in the mastopathy as well as in the subsequent breast cancer. These two mutations, however, could also be due to fixation artifacts. Conclusion: Since no significant somatic mutations in the fibrocystic breast tissue, and only doubtful shared mutations between benign and associated cancer tissue were detected, it remains unclear why women with fibrocystic breast disease have a statistically significant increased risk of breast cancer. Further analyses, maybe on the level of gene expression, could help to clarify the role of these benign alterations in the development of breast cancer and help to identify women at greater risk of developing subsequent invasive cancer.
| S-EPMC6667637 | biostudies-literature
Project description:BackgroundBenign breast disease (BBD) increases the risk of breast cancer, but details of the relationship would benefit from further study in the UK.MethodsAnalysis of linked statistical abstracts of hospital data, including a cohort of 20 976 women with BBD in an Oxford data set and 89 268 such women in an English national data set.ResultsRate ratios (RRs) for breast cancer, comparing BBD and comparison cohorts in these two data sets, were 2.3 (95% CI: 2.2-2.5) and 3.2 (3.0-3.3), respectively. RRs rose with increasing age at BBD diagnosis and remained elevated for at least 20 years after diagnosis. RRs were particularly high for a relatively small number of cancers occurring in the first few months after BBD diagnosis.ConclusionsOur findings accord well with those in other large studies, mostly done in the USA, in showing a sustained long-term cancer risk after BBD. They also demonstrate that known long-term risks of disease can be reliably identified from linked routine administrative hospital statistics. Most other studies omit cancers in the first few months after BBD. Such cases-presumably either misdiagnosed or miscoded-merit further study to determine whether in fact they include diagnoses of cancer that were initially missed.
| S-EPMC2990391 | biostudies-literature
Project description:MicroRNAs are endogenous, small non-coding RNAs that control gene expression by directing their target mRNAs for degradation and/or posttranscriptional repression. Abnormal expression of microRNAs is thought to contribute to the development and progression of cancer. A history of benign breast disease (BBD) is associated with increased risk of subsequent breast cancer. However, no large-scale study has examined the association between microRNA expression in BBD tissue and risk of subsequent invasive breast cancer (IBC). We conducted discovery and validation case-control studies nested in a cohort of 15,395 women diagnosed with BBD in a large health plan between 1971 and 2006 and followed to mid-2015. Cases were women with BBD who developed subsequent IBC; controls were matched 1:1 to cases on age, age at diagnosis of BBD, and duration of plan membership. The discovery stage (316 case-control pairs) entailed use of the Illumina MicroRNA Expression Profiling Assay (in duplicate) to identify breast cancer-associated microRNAs. MicroRNAs identified at this stage were ranked by the strength of the correlation between Illumina array and quantitative PCR results for 15 case-control pairs. The top ranked 14 microRNAs entered the validation stage (165 case-control pairs) which was conducted using quantitative PCR (in triplicate). In both stages, linear regression was used to evaluate the association between the mean expression level of each microRNA (response variable) and case-control status (independent variable); paired t-tests were also used in the validation stage. None of the 14 validation stage microRNAs was associated with breast cancer risk. The results of this study suggest that microRNA expression in benign breast tissue does not influence the risk of subsequent IBC.
| S-EPMC5809016 | biostudies-literature
Project description:Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm(2), median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0-10; 11-20; 21-30; 31-50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96-6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13-7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03-11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40-10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US.
| S-EPMC5045857 | biostudies-literature
Project description:Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk.We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided.Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses.Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.
| S-EPMC3714021 | biostudies-other
Project description:The majority of studies have reported risks of breast cancer (BC) from benign breast disease (BBD) in essentially homogenous Caucasian populations. Information on breast cancer risk factors in larger, multi-ethnic populations should facilitate the development of appropriate and targeted risk reduction strategies.Cases and controls were drawn from a parent BBD cohort of 4,970 women, 1,341 African-Americans (AA) and 3,629 non-AA who were diagnosed with BBD after examination of an excisional breast biopsy. Risk factors (34 variables) included demographics, lesion types, and epidemiological variables.The final multivariable model retained significance (P < 0.05) for lesion risk-level, fibroadenoma, and the interaction of age-by-race. Women with proliferative lesions (no atypia, risk level 2) were 1.7 times more likely to develop BC when compared with women with non-proliferative lesions (OR = 1.7, 95% CI 1.13, 2.42, P = 0.009). Women with atypia (risk level 3) were 3.75 times more likely to develop BC compared to women with non-proliferative lesions (OR = 3.75, 95% CI 1.99, 7.06, P < 0.001). The odds of breast cancer was approximately 35% lower among women with fibroadenoma as compared to women without fibroadenoma (OR = 0.65, 95% CI 0.46, 0.94, P = 0.020). AA women with BBD who were 50 years or older were 2.28 times more likely to develop breast cancer as compared to non-AA women who were less than 50 years old (OR = 2.28, 95% CI 1.34, 3.88, P = 0.002).Women with fibroadenoma (nonproliferative or proliferative) were less likely to progress to BC. Older AA women are at greater risk for progression to breast cancer from BBD.
| S-EPMC3715322 | biostudies-literature