Servicio General de Citometría, Departamento de Medicina and Centro de Investigación del Cáncer (IBMCC-CSIC/USAL), Universidad de Salamanca, Salamanca, Spain.
PLoS One. 2011;6(7):e22315. doi: 10.1371/journal.pone.0022315. Epub 2011 Jul 21.
The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP)-arrays to define those chromosomal regions which most commonly harbour copy number (CN) alterations and loss of heterozygozity (LOH) in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70%) extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9) versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11). From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterozygozity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC.
与胰腺导管腺癌相关的特定基因和遗传途径在很大程度上仍然未知，部分原因是迄今为止应用于这些研究的技术分辨率较低。在这里，我们使用高密度 500K 单核苷酸多态性 (SNP) 阵列来定义那些最常见的染色体区域，这些区域在一系列 20 个 PDAC 肿瘤中经常发生拷贝数 (CN) 改变和杂合性丢失 (LOH)，并将相应的遗传特征与疾病的最相关临床和组织病理学特征相关联。总的来说，我们的结果表明，原发性 PDAC 经常表现出 (>70%) 染色体 1q、7q、8q 和 20q 的广泛增益，以及染色体 1p、9p、12q、17p 和 18q 的丢失，这些染色体区域包含多个癌症和 PDAC 相关基因。有趣的是，这些改变聚类为两个不同的遗传特征，其特征为 2q14.2、3q22.1、5q32、10q26.13、10q26.3、11q13.1、11q13.3、11q13.4、16q24.1、16q24.3、22q13.1、22q13.31 和 22q13.32 染色体区域的增益 (第 1 组；n = 9)，与 1q21.1 的增益和 1p36.11、6q25.2、9p22.1、9p24.3、17p13.3 和 Xp22.33 染色体区域的丢失 (第 2 组；n = 11)。从临床和组织病理学的角度来看，第 1 组病例与较小且分化良好的 I/II 级 PDAC 肿瘤相关，而第 2 组 PDAC 肿瘤较大，主要由分化不良的 III 级癌组成。这些发现证实了 PDAC 的细胞遗传学复杂性和杂合性，并为肿瘤细胞遗传学与其组织病理学特征之间的关联提供了证据。此外，我们还表明，鉴定出的改变区域包含多个癌症相关基因，值得进一步研究以确定它们在 PDAC 发病机制中的相关性。
