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Int7G24A Variant of Transforming Growth Factor-ß Receptor Type I Is Associated with Invasive Breast Cancer

Authors' Affiliations: ¹ Wood Hudson Cancer Research Laboratory, Newport, Kentucky; ² Department of Pathology and Laboratory Medicine, St. Elizabeth Medical Center, Edgewood, Kentucky; ³ Department of Mathematical Sciences, University of Cincinnati, Cincinnati, Ohio; and ⁴ Lilly Research Laboratory, Cancer Cell Growth & Translational Genetics, Eli Lilly & Co., Indianapolis, Indiana

Requests for reprints: Taiping Chen, Wood Hudson Cancer Research Laboratory, 931 Isabella Street, Newport, KY 41071-4701. Phone: 859-581-7249; Fax: 859-581-2392; E-mail: tchen{at}woodhudson.org.

Purpose: The transforming growth factor-ß (TGF-ß) signaling pathway has been frequently implicated in breast cancer. An intronic variant (Int7G24A) of TGF-ß receptor type I (TGFBR1) is associated with kidney and bladder cancers in our recent study. We hypothesize that this germline variant may be involved in development and progression of breast cancer.

Experimental Design: Case-control studies were designed from archived paraffin-embedded tissue specimens from the same geographic area with a homogenous ethnic population. We analyzed 223 patients (25 with preinvasive tumors and 198 with invasive and metastatic breast cancers) and 153 noncancer controls. The Int7G24A was identified by PCR-RFLP. Another germline deletion (TGFBR1*6A) and somatic mutations in the TGFBR1 were also analyzed by PCR and single-strand conformational polymorphism.

Results: The Int7G24A allele was evident in 32% of patients with preinvasive neoplasms and 48% of patients with invasive breast cancers compared with 26% controls (P = 0.00008). In addition, 11 (5.6%) homozygous Int7G24A carriers were found in patients with invasive breast cancers, whereas only 3 (2%) homozygous carriers were found in the control group. The TGFBR1*6A allele was not significantly associated with breast cancer patients and only one somatic mutation was found in 71 breast cancers.

Conclusion: These data suggest that the germline Int7G24A variant may represent a risk factor for invasive breast cancer and a marker for breast cancer progression. A separate study with a larger sample size is warranted to validate the association of the Int7G24A with human breast cancer.

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