Jinawath Natini, Shiao Meng-Shin, Norris Alexis, Murphy Kathleen, Klein Alison P, Yonescu Raluca, Iacobuzio-Donahue Christine, Meeker Alan, Jinawath Artit, Yeo Charles J, Eshleman James R, Hruban Ralph H, Brody Jonathan R, Griffin Constance A, Harada Shuko
Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Genes Chromosomes Cancer. 2017 May;56(5):427-435. doi: 10.1002/gcc.22447. Epub 2017 Mar 7.
Pancreatic ductal adenocarcinoma (PDAC), either sporadic or familial, has a dismal prognosis and finding candidate genes involved in development of the cancer is crucial for the patient care. First, we identified two patients with germline alterations in or adjacent to CDH10 by chromosome studies and sequencing analyses in 41 familial pancreatic cancer (FPC) cases. One patient had a balanced translocation between chromosome 5 and 20. The breakpoint on chromosome band 5p14.2 was ∼810 Kb upstream of CDH10, while that on chromosome arm 20p was in the pericentromeric region which might result in inactivation of one copy of the gene leading to reduced expression of CDH10. This interpretation was supported by loss of heterozygosity (LOH) seen in this region as determined by short tandem repeat analyses. Another patient had a single nucleotide variant in exon 12 (p.Arg688Gln) of CDH10. This amino acid was conserved among vertebrates and the mutation was predicted to have a pathogenic effect on the protein by several prediction algorithms. Next, we analyzed LOH status in the CDH10 region in sporadic PDAC and at least 24% of tumors had evidence of LOH. Immunohistochemical stains with CDH10 antibody showed a different staining pattern between normal pancreatic ducts and PDAC. Taken together, our data supports the notion that CDH10 is involved in sporadic pancreatic carcinogenesis, and might have a role in rare cases of FPC. Further functional studies are needed to elucidate the tumor suppressive role of CDH10 in pancreatic carcinogenesis.
胰腺导管腺癌（PDAC），无论是散发性还是家族性，预后都很差，找到参与该癌症发生发展的候选基因对患者治疗至关重要。首先，我们通过染色体研究和测序分析，在41例家族性胰腺癌（FPC）病例中，鉴定出两名CDH10基因内或其邻近区域存在种系改变的患者。一名患者的5号和20号染色体之间存在平衡易位。5号染色体带5p14.2上的断点位于CDH10上游约810 Kb处，而20号染色体臂20p上的断点位于着丝粒周围区域，这可能导致该基因的一个拷贝失活，从而导致CDH10表达降低。短串联重复序列分析确定该区域存在杂合性缺失（LOH），支持了这一解释。另一名患者的CDH10基因外显子12存在单核苷酸变异（p.Arg688Gln）。该氨基酸在脊椎动物中保守，几种预测算法预测该突变对蛋白质具有致病作用。接下来，我们分析了散发性PDAC中CDH10区域的LOH状态，至少24%的肿瘤有LOH证据。用CDH10抗体进行免疫组化染色显示，正常胰腺导管和PDAC之间的染色模式不同。综上所述，我们的数据支持CDH10参与散发性胰腺癌发生的观点，并且可能在罕见的FPC病例中起作用。需要进一步的功能研究来阐明CDH10在胰腺癌发生中的肿瘤抑制作用。
