Abstract 3359: Prevalence of heterozygous and homozygous 9p21 deletions in human cancer: a tissue microarray study on 4999 tumors from 125 different tumor types

Abstract 9p21 deletions including CDKN2A belong to the most common chromosomal aberrations in cancer. Most of the topical interest in 9p21 comes S-methyl-5′-thioadenosine phosphorylase (MTAP) which is also included in most 9p21 deletions. Homozygous 9p21 deletions are the major cause for MTAP deficiency which results in a critical vulnerability of cancer cells towards drugs targeting several different pathways. Fluorescence in situ hybridization (FISH) is the gold standard method for deletion detection because single cells are always analyzed independent of any admixture of non-neoplastic cells. To assess the prevalence of heterozygous and homozygous deletions in cancer, a tissue microarray containing 7, 172 samples from 125 different tumor entities was analyzed by FISH. Consecutive sections were immunostained for MTAP and p16. Among 4, 999 evaluable cases, 10.7% had a heterozygous and 7.4% a homozygous deletion. Heterozygous and homozygous did not predominate in the same tumor categories. Homozygous deletions were most frequent in mesotheliomas (up to 47.8%), pancreatic ductal adenocarcinoma (44, 7%), and in urothelial carcinoma (up to 36.4%) while the heterozygous deletions were most common in squamous cell carcinomas (up to 34.3%), leiomyosarcoma (31.4%), adenocarcinomas of the esophagus (30.1%), malignant melanoma (29.4%), and cholangiocarcinoma (21.2%). Accordingly, the proportion of homozygous deletions within the 9p21 deleted cases varied markedly. It was high in mesothelioma (up to 91.7%), urothelial carcinoma (up to 80%), pancreatic ductal adenocarcinoma (76.4%), and mucinous carcinoma of the ovary (66.7%). It was intermediate in squamous cell carcinomas of different organs (10-50%) and adenocarcinoma of the lung (46.3%), and it was particularly low in endometrioid (9.1%) and in high-grade serous (4%) carcinoma of the ovary. Both MTAP and p16 were not detectable in cancers with 9p21 deletion, but otherwise the results differed markedly between these proteins. The expression of MTAP was markedly lower in heterozygously deleted cancers as in wild type cancers (p<0.0001) while p16 expression did not change significantly from normal to heterozygously deleted cases. In summary, these data provide a unique FISH based catalogue of 9p21 deletions in cancer and demonstrate that the proportions of heterozygous and homozygous MTAP deletions vary markedly between tumor entities. The near perfect concordance between homozygous MTAP deletions and absence of MTAP immunostaining further supports the use of IHC for detecting MTAP deficiency. Citation Format: Natalia Gorbokon, Katharina Teljuk, Katharina Möller, Seyma Büyücek, Maximilian Lennartz, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Elena Bady, Lisa Hornsteiner, Guido Sauter, Ronald Simon, Stefan Steurer, David Dum, Sarah Minner, Frank Jacobsen, Till S Clauditz, Martina Kluth. Prevalence of heterozygous and homozygous 9p21 deletions in human cancer: a tissue microarray study on 4999 tumors from 125 different tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3359.