Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Pediatr Blood Cancer. 2013 May;60(5):754-60. doi: 10.1002/pbc.24453. Epub 2013 Jan 9.
Shwachman-Diamond syndrome (SDS) is characterized by hypoplasia of the bone marrow and exocrine pancreas and a high risk of leukemia. It is unknown whether solid tumors are part of the disease phenotype.
We performed copy number alterations using Affymetrix human SNP 6.0 array. Furthermore, we did direct sequencing of pancreatic cancer-related genes and immunohistochemical expression of selective proteins.
Among 41 patients with SDS who enrolled on the registry, we identified one male patient with a solid tumor: moderately differentiated pancreatic ductal adenocarcinoma. The tumor harbored 41 copy number alterations (CNAs) and had no regions of loss of heterozygosity (LOH). None of these CNAs were exclusive to the tumor. One copy of the tumor suppressor genes CTNNA3 and LGALS9C was lost in both the peripheral blood and tumor. Direct sequencing of TP53, KRAS, and NRAS revealed no mutations. Immunohistochemical staining for cyclin D1, E-cadherin, p53 MLH1 and MSH2 and β-catenin, was similar to that seen in non-hereditary pancreatic cancer.
Our case raises the possibility that solid tumors are associated with SDS, thereby broadening the clinical phenotype of the disease. The relatively young age at cancer diagnosis and the specific involvement of the pancreas make the possibility of an association with SDS likely. Similar to leukemia in SDS, the pancreatic cancer developed in hypoplastic tissues. This observation and the relative genomic stability of the tumor strengthen the hypothesis of improved adaptation of malignant clones among a population of disadvantaged cells as a mechanism for tumor expansion in SDS.
Shwachman-Diamond 综合征（SDS）的特征为骨髓和外分泌胰腺发育不良，以及罹患白血病的风险较高。目前尚不清楚实体肿瘤是否属于该疾病的表型。
我们采用 Affymetrix 人类 SNP 6.0 阵列进行拷贝数改变分析。此外，我们还对胰腺癌相关基因进行了直接测序，并对选择性蛋白进行了免疫组织化学表达分析。
在登记在册的 41 名 SDS 患者中，我们发现了一名男性患者患有实体瘤：中分化胰腺导管腺癌。该肿瘤存在 41 个拷贝数改变（CNA），并且没有杂合性丢失（LOH）区域。这些 CNA 没有一个是肿瘤所特有的。肿瘤抑制基因 CTNNA3 和 LGALS9C 的一个拷贝在外周血和肿瘤中均丢失。TP53、KRAS 和 NRAS 的直接测序未发现突变。Cyclin D1、E-cadherin、p53 MLH1 和 MSH2 以及β-catenin 的免疫组化染色与非遗传性胰腺癌相似。
我们的病例提示实体瘤可能与 SDS 相关，从而拓宽了该疾病的临床表型。癌症诊断时的相对年轻年龄和胰腺的特定受累使 SDS 相关性的可能性增加。与 SDS 中的白血病相似，该胰腺肿瘤发生在发育不良的组织中。这一观察结果以及肿瘤相对基因组稳定性，支持了在细胞劣势人群中恶性克隆适应性提高作为 SDS 中肿瘤扩张机制的假说。
