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Lack of HIN-1 Methylation in BRCA1-linked and "BRCA1-like" Breast Tumors¹

Departments of Medical Oncology [I. K., J. L-D., K. P.], and Biostatistics [R. G.], Dana-Farber Cancer Institute and Harvard Medical School [I. K., K. P.] and Department of Pathology, Brigham and Women’s Hospital [G. L., A. R.], Boston, Massachusetts; Karolinska Hospital, Stockholm, Sweden [P. M., A. L.]; Laboratory of Cell Biology, Department of Pathology, University Hospital of Iceland, Iceland [H. K. J., R. B. B.]; Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland [H. N.]; and Department of Oncology, University Hospital of Lund, Lund, Sweden [A. B.]

We recently identified a candidate tumor suppressor gene, HIN-1, that is silenced due to methylation in the majority of sporadic breast carcinomas and is localized to 5q33-qter, an area frequently lost in BRCA1 tumors and thought to harbor a BRCA1 modifier gene. To establish whether germ-line mutations in HIN-1 may influence breast cancer risk, we sequenced the HIN-1 coding region in 10 familial breast cancer patients with positive logarithm of the odds scores of at least one of the markers flanking HIN-1. We also sequenced the HIN-1 coding region in 15 BRCA1 and 35 sporadic breast tumors to determine whether HIN-1 is the target of the frequent 5q loss in BRCA1 tumors. No sequence alterations were found in any of the cases analyzed. However, analysis of HIN-1 promoter methylation status revealed that in striking contrast to sporadic cases, there is a nearly complete lack of HIN-1 methylation in BRCA1 tumors (P < 0.0001). Sporadic breast tumors with a "BRCA1-like" histopathological phenotype also demonstrated significantly lower frequency of HIN-1 promoter methylation (P = 0.01) compared with other cancer types, and there was also a difference among tumors based on their estrogen receptor and HER2 status (P = 0.006), suggesting that HIN-1 methylation patterns are associated with specific breast cancer subtypes.

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