1. ¹Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
2. ²Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
3. ³Salmedix, Inc, San Diego, CA, USA
4. ⁴Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
5. ⁵Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
6. ⁶Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
7. ⁷McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence: Dr A Maitra, MBBS, Department of Pathology, Ross 632, 720 Rutland Avenue, Baltimore, MD 21205, USA. E-mail: amaitra1@jhmi.edu

Received 10 June 2004; Revised 14 December 2004; Accepted 14 December 2004; Published online 8 April 2005.

Abstract

The p16INK4A/CDKN2A (p16) gene on chromosome 9p21 is inactivated in >90% of invasive pancreatic cancers. In 40% of pancreatic cancers the p16 gene is inactivated by homozygous deletion, in 40% by an intragenic mutation coupled with loss of the second allele, and in 10–15% by hypermethylation of the p16 gene promoter. Immunohistochemical labeling for the p16 gene product parallels gene status, but does not provide information of the mechanism of p16 gene inactivation. The methylthioadenosine phosphorylase gene (MTAP) gene also resides on chromosome 9p21, approximately 100 kb telomeric to the p16 gene. The MTAP gene is frequently contained within p16 homozygous deletions, producing concordant loss of both p16 and MTAP gene expression. Concordant loss of both p16 and MTAP protein expression can therefore be used as a surrogate marker for p16 homozygous deletion. Here we immunolabeled a series of pancreatic intraepithelial neoplasia (PanIN) lesions of various histologic grades for the p16 and MTAP gene products using a high-throughput PanIN tissue microarray (TMA) format. We demonstrate concordant loss of p16 and MTAP protein expression in 6/73 (8%) PanINs, including five high-grade lesions and one low-grade lesion. Immunolabeling for both p16 and MTAP protein expression provides a tool to evaluate tissues with intact morphology for p16 gene homozygous deletions. The concordant loss of expression of both genes in PanIN lesions demonstrates that homozygous deletions of the p16 tumor suppressor gene can occur in noninvasive precursor lesions.