Background: The complete loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression, often due to homozygous 9p21 deletion, creates a druggable vulnerability in cancer cells. Methods: A total of 769 primary pancreatic ductal adenocarcinomas were analyzed on tissue microarrays with MTAP immunohistochemistry (IHC) and 9p21 fluorescence in situ hybridization (FISH). Intratumoral heterogeneity was assessed on a “heterogeneity” TMA containing up to nine samples from different areas of 236 primary tumor and nodal metastases, and whole sections of all tumor blocks from 19 cancers. Results: MTAP expression loss was found in 181 (37.9%) of 478 interpretable primary tumors and was unrelated to pT, pN, grade, and tumor size. MTAP expression loss was homogenous in 37.6% and heterogeneous in 1.1% of the 181 tumors, with at least three evaluable samples on the heterogeneity TMA. On whole sections, 1 of 19 tumors showed heterogeneous MTAP loss. The correlation between IHC and FISH was nearly perfect, with 98.8% of MTAP-deficient samples showing a 9p21 deletion. Conclusions: MTAP expression loss is frequent, caused by homozygous deletion, and mostly homogeneous in pancreatic ductal adenocarcinomas. Considering also their aggressive clinical behavior, pancreatic adenocarcinomas may represent an ideal cancer type for studying new drugs targeting MTAP-deficient cancer cells in clinical trials.
背景：S-甲基-5′-硫代腺苷磷酸化酶（MTAP）表达的完全缺失（通常由9p21纯合性缺失引起）在癌细胞中形成了可靶向治疗的脆弱性。方法：通过组织芯片技术对769例原发性胰腺导管腺癌进行MTAP免疫组化（IHC）和9p21荧光原位杂交（FISH）分析。利用包含236例原发肿瘤及淋巴结转移灶不同区域（最多9个样本）的“异质性”组织芯片，以及19例癌症全部肿瘤石蜡块的整体切片，评估肿瘤内异质性。结果：在478例可评估的原发肿瘤中，181例（37.9%）出现MTAP表达缺失，该现象与pT分期、pN分期、分级及肿瘤大小无关。在异质性组织芯片至少有三个可评估样本的181例肿瘤中，37.6%呈现均质性MTAP缺失，1.1%呈异质性缺失。整体切片分析显示，19例肿瘤中有1例存在异质性MTAP缺失。IHC与FISH结果高度一致，98.8%的MTAP缺失样本均显示9p21缺失。结论：MTAP表达缺失在胰腺导管腺癌中较为常见，主要由纯合性缺失引起且多呈均质性分布。结合其侵袭性临床行为，胰腺腺癌可能成为临床试验中研究靶向MTAP缺陷癌细胞新型药物的理想模型。
Deficiency of MTAP Is Frequent and Mostly Homogeneous in Pancreatic Ductal Adenocarcinomas
肿瘤(癌症)患者之家