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Cancer Genes and Genomics

Frequent HIN-1 Promoter Methylation and Lack of Expression in Multiple Human Tumor Types¹

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, ² Harvard Medical School, and ³ Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts; ⁴ Laboratory of Population Genetics, National Cancer Institute, Bethesda, Maryland; ⁵ University of Nebraska Medical Center, Omaha, Nebraska; ⁶ Institute of Cancer Genetics, Department of Pathology, Columbia University, New York, New York; ⁷ Stanford University, Stanford, California; and ⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Kornelia Polyak, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D740C, Boston, MA 02115. Phone: 617-632-2106; Fax: 617-632-4005. E-mail: Kornelia_Polyak{at}dfci.harvard.edu

HIN-1 (high in normal-1) is a candidate tumor suppressor identified as a gene silenced by methylation in the majority of breast carcinomas. HIN-1 is highly expressed in the mammary gland, trachea, lung, prostate, pancreas, and salivary gland, and in the lung, its expression is primarily restricted to bronchial epithelial cells. In this report, we show that, correlating with the secretory nature of HIN-1, high levels of HIN-1 protein are detected in bronchial lavage, saliva, plasma, and serum. To determine if, similar to breast carcinomas, HIN-1 is also silenced in tumors originating from other organs with high HIN-1 expression, we analyzed its expression and promoter methylation status in lung, prostate, and pancreatic carcinomas. Nearly all prostate and a significant fraction of lung and pancreatic carcinomas showed HIN-1 hypermethylation, and the majority of lung and prostate tumors lacked HIN-1 expression. In lung carcinomas, the degree of HIN-1 methylation differed among tumor subtypes (P = 0.02), with the highest level of HIN-1 methylation observed in squamous cell carcinomas and the lowest in small cell lung cancer. In lung adenocarcinomas, the expression of HIN-1 correlated with cellular differentiation status. Hypermethylation of the HIN-1 promoter was also frequently observed in normal tissue adjacent to tumors but not in normal tissue from noncancer patients, implying that HIN-1 promoter methylation may be a marker of premalignant changes. Thus, silencing of HIN-1 expression and methylation of its promoter occurs in multiple human cancer types, suggesting that elimination of HIN-1 function may contribute to several forms of epithelial tumorigenesis.

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