Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer

AbstractIt is largely unknown how the risk of development of breast cancer is transduced by somatic genetic alterations. To address this lacuna of knowledge and acknowledging that benign breast disease (BBD) is an established risk factor for breast cancer, we established a case-control study: The Benign Breast & Cancer Risk (BBCAR) Study. Cases are women with BBD who developed subsequent invasive breast cancer (IBC) at least 3 years after the biopsy and controls are women with BBD who did not develop IBC (median follow-up 16.6 years). We selected 135 cases and individually matched controls (1:2) to cases based on age and type of benign disease: non-proliferative or proliferation without atypia. Whole exome sequencing was performed on DNA from the benign lesions and from subsets with available germline DNA or tumor DNA. Although the number of cases and controls with copy number variation data is limited, several amplifications and deletions are exclusive to the cases. In addition to two known mutational signatures, a novel signature was identified that is significantly (p=0.007) associated with triple negative breast cancer. The somatic mutation rate in benign lesions is similar to that of invasive breast cancer and does not differ between cases and controls. Two mutated genes are significantly associated with time to the diagnosis of breast cancer, and mutations shared between the benign biopsy tissue and the breast malignancy for the ten cases for which we had matched pairs were identified. BBD tissue is a rich source of clues to breast oncogenesis.One Sentence SummaryGenetic aberrations in benign breast lesions distinguish breast cancer cases from controls and predict cancer risk.

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Somatic mutations in benign breast disease tissues and association with breast cancer risk

BMC Medical Genomics ◽

10.1186/s12920-021-01032-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Stacey J. Winham ◽

Chen Wang ◽

Ethan P. Heinzen ◽

Aditya Bhagwate ◽

Yuanhang Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Somatic Mutations ◽

Benign Breast Disease ◽

Breast Disease ◽

Allele Frequencies ◽

Cancer Development ◽

Permutation Testing ◽

Mutational Burden ◽

Gene Level

Abstract Background Benign 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. Methods A 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. Results After 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). Conclusions Somatic 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.

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Infiltrating immune cells in benign breast disease and risk of subsequent invasive breast cancer

Breast Cancer Research ◽

10.1186/s13058-021-01395-x ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Thomas E. Rohan ◽

Rhonda Arthur ◽

Yihong Wang ◽

Sheila Weinmann ◽

Mindy Ginsberg ◽

...

Keyword(s):

Breast Cancer ◽

Immune Response ◽

Invasive Breast Cancer ◽

Normal Tissue ◽

Benign Breast Disease ◽

Immune Cell ◽

Menopausal Status ◽

Lymphocytic Infiltration ◽

Breast Disease ◽

Cell Counts

Abstract Background It is well established that tumors are antigenic and can induce an immune response by the host, entailing lymphocytic infiltration of the tumor and surrounding stroma. The extent and composition of the immune response to the tumor, assessed through evaluation of tumor-infiltrating lymphocyte counts, has been shown in many studies to have prognostic and predictive value for invasive breast cancer, but currently, there is little evidence regarding the association between infiltrating immune cell counts (IICCs) in women with benign breast disease (BBD) and risk of subsequent invasive breast cancer. Methods Using a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest, we conducted a nested case-control study in which cases were women who developed a subsequent invasive breast cancer during follow-up and controls were individually matched to cases on age at BBD diagnosis. We assessed IICCs in normal tissue and in the BBD lesions, and we used unconditional logistic regression to estimate the multivariable odds ratios (OR) and 95% confidence intervals (CI) for the associations between IICCs and breast cancer risk. Results There was no association between the IICC in normal tissue (multivariable OR per 5% increase in IICC = 1.05, 95% CI = 0.96–1.16) or in the BBD lesion (OR per 5% increase in IICC = 1.06, 95% CI = 0.96–1.18) and risk of subsequent invasive breast cancer. Also, there were no associations within subgroups defined by menopausal status, BBD histology, BMI, and history of smoking. Conclusion The results of this study suggest that IICCs in BBD tissue are not associated with altered risk of subsequent invasive breast cancer.

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Somatic Mutations in Benign Breast Disease Tissues and Association With Breast Cancer Risk

10.21203/rs.3.rs-257991/v1 ◽

2021 ◽

Author(s):

Stacey Winham ◽

Chen Wang ◽

Ethan P. Heinzen ◽

Aditya Bhagwate ◽

Yuanhang Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Somatic Mutations ◽

Benign Breast Disease ◽

Breast Disease ◽

Allele Frequencies ◽

Cancer Development ◽

P Values ◽

Mutational Burden ◽

Gene Level

Abstract Background: Benign 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. Methods: A 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 tested and 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 burden tests, SKAT-O and logistic regression, and adjusted for clinical and technical covariates including epithelial percentage, histologic impression, patient age and year of BBD biopsy. Results: After filtering, the variant frequency of SNPs in our samples was highly consistent with population allele frequencies reported in 1KG/ExAC (0.986, p <1e-16). Ten genes were found to be associated with later cancer status by four of 12 association methods, with nominal p-values <0.05: MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1. Additionally, analysis revealed 11 and 19 gene-level associations with p-values <0.05 and OR<1 for all cancer cases and ER- cases, respectively. 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=0.003).Conclusions: Somatic 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.

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