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Deep sequencing across germline genome-wide association study signals relating to breast cancer events in women receiving aromatase inhibitors for adjuvant therapy of early breast cancer

Ingle, James N.a,,*; Kalari, Krishna R.b,,*; Momozawa, Yukihidef; Kubo, Michiakif; Furukawa, Yoichif; Shepherd, Lois E.g; Ellis, Matthew J.d; Goss, Paul E.e; Barman, Poulamib; Carlson, Erin E.b; Sinnwell, Jason P.b; Tang, Xiaojiab; Goetz, Matthew P.a; Chen, Bingshu E.g; Cairns, Junmeic; Weinshilboum, Richard M.c; Wang, Lieweic

doi: 10.1097/FPC.0000000000000382
Original Articles

Objective To identify additional genetic variants beyond those observed in a previous genome-wide association study (GWAS) in women treated on the MA.27 clinical trial in which women were randomized to 5 years of adjuvant therapy with anastrozole or exemestane.

Patients and methods We performed a matched case–control study in 234 women who had a recurrence of breast cancer (cases) and 649 women who had not (controls). The analysis was restricted to White women with an estrogen receptor-positive breast cancer. Multiplex PCR-based targeted deep sequencing was performed of the MIR2052HG region on chromosome 8 between positions 75.4 and 75.7, a span of 300 kb, in an attempt to identify additional functional single nucleotide polymorphisms (SNPs).

Results A total of 4677 unique variants were identified that had not been identified in the previous GWAS. Clinical Annotation of Variants analysis revealed 10 variants, including eight SNPs and two insertion–deletion mutations with moderate or high impact. However, none of the common and variant regions was significant after adjustment for the most significant SNP (rs13260300) identified in our previous GWAS. We performed haplotype analysis that revealed two regions in which the haplotypes lost significance when adjusted for this prior GWAS SNP and one region with two significant haplotypes (P = 0.046 and 0.031) after adjusting for the GWAS SNP.

Conclusion We were unable to identify common or rare variant regions that added value to the findings from our previous GWAS. We did find two haplotypes that were significant after adjusting for our top GWAS SNP but these were considered to be of marginal value.

aDepartment of Oncology

bDepartment of Health Sciences Research

cDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota

dDepartment of Oncology, Baylor College of Medicine, Houston, Texas

eDepartment of Oncology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA

fRIKEN Center for Integrative Medical Sciences, Yokohama, Japan

gCanadian Cancer Trials Group, Kingston, Ontario, Canada

* James N. Ingle and Krishna R. Kalari contributed equally to the writing of this article.

Received 10 April 2019 Accepted 23 May 2019

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Correspondence to James N. Ingle, MD, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA Tel: + 1 507 284 3731; fax: + 1 507 284 1803; e-mail:

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