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Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women.

ABSTRACT: Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.All samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes.The study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADH (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and ?3 foci, respectively; P for linear trend = .006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and ?3 foci, respectively; P for linear trend = .001). In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and ?3 foci, respectively (P for linear trend < .001); for ALH, the relative risks also increased but not significantly (2.61, 3.48, and 4.02, respectively; P = .148). When the Mayo and Nashville samples were combined, the risk increased significantly for 1, 2, and ?3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P < .001) and 2.58, 3.49, and 4.97, respectively, for ALH (P = .001).In 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long-term BC risk for ADH and ALH. Cancer 2016;122:2971-2978. © 2016 American Cancer Society.

SUBMITTER: Degnim AC

PROVIDER: S-EPMC5030128 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women.

Degnim Amy C AC Dupont William D WD Radisky Derek C DC Vierkant Robert A RA Frank Ryan D RD Frost Marlene H MH Winham Stacey J SJ Sanders Melinda E ME Smith Jeffrey R JR Page David L DL Hoskin Tanya L TL Vachon Celine M CM Ghosh Karthik K Hieken Tina J TJ Denison Lori A LA Carter Jodi M JM Hartmann Lynn C LC Visscher Daniel W DW

Cancer 20160628 19

<h4>Background</h4>Women with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.<h4>Methods</h4>All samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratif ...[more]

PMID: 27352219

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Project description:INTRODUCTION: Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese. METHODS: In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth). RESULTS: Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting (AUC: 0.637, 95% CI: 0.619 to 0.655; sensitivity = 62.16%, specificity = 60.03%) (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676) (sensitivity = 61.98%, specificity = 60.26%) was obtained for the combination of five marker SNPs, age at menarche and age at first live birth. CONCLUSIONS: This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment.

Project description:BackgroundAtypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation.MethodsIn this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues.ResultsA 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels.ConclusionsThe alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

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Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women.

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Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women.

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