Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion
Open accessAbstract
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.
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The location of the methylthioadenosine phosphorylase gene (MTAP) is adjacent to CDKN2A.
“The location of the methylthioadenosine phosphorylase gene (MTAP) is adjacent to CDKN2A and the majority of PDAC tumors with CDKN2A loss also had MTAP loss57–59.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [57]
The majority of PDAC tumors with CDKN2A loss also had MTAP loss.
“The location of the methylthioadenosine phosphorylase gene (MTAP) is adjacent to CDKN2A and the majority of PDAC tumors with CDKN2A loss also had MTAP loss57–59.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [57]
About 40% of pancreatic ductal adenocarcinomas have both mutated TP53 and deleted ARF.
“For example, approximately 40% of pancreatic ductal adenocarcinomas have mutated TP53 and deleted ARF (Heinmoller, et al., 2000; Hustinx, et al., 2005; Maitra, et al., 2003).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Hustinx, et al., 2005
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- Authors
- Hustinx, S. R., Leoni, L. M., Yeo, C. J., Brown, P. N., Goggins, M., Kern, S. E., Hruban, R. H., & Maitra, A.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Johns Hopkins Hospital (US)
- Johns Hopkins University (US)
- Corresponding author
- Maitra, Anirban
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 18
- Issue
- 7
- Pages
- 959-963
- ISSN
- 0893-3952 (ISSN-L)
- OpenAlex
- W1991870390
- Cited by
- 125
- References
- 30
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 9 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 4 · 2015: 10 · 2014: 9 · 2013: 6 · 2012: 6
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Rolfe Pancreatic Cancer Foundation
- National Institutes of Health (CA62924)
- National Cancer Institute (P50CA062924, CA 62924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- MTAP, homozygous deletion, pancreatic intraepithelial neoplasia, chromosome 9p21, tumor suppressor, pancreatic cancer precursor lesions, immunohistochemical markers, tissue microarray
- MeSH terms
- Homozygote, Humans, Immunohistochemistry, Neoplasm Invasiveness, Pancreatic Neoplasms, Precancerous Conditions, Purine-Nucleoside Phosphorylase, Gene Deletion, Cyclin-Dependent Kinase Inhibitor p16
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