Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy

Abstract

The virtual lack of well-characterized metastatic pancreatic cancer tissues for study has limited systematic studies of the metastatic process of this deadly disease. To address this important issue, we have instituted a rapid autopsy protocol for the collection of high quality tissues from patients with metastatic pancreatic cancer, called the Gastrointestinal Cancer Rapid Medical Donation Program (GICRMDP). At the time of preparation of this manuscript, 20 patients with metastatic pancreatic cancer and one patient with metastatic colon cancer have undergone a rapid autopsy in association with the GICRMDP. The average time interval achieved for these 21 patients was 8.0 hours, with more than 500 individual samples of matched high quality primary and metastatic pancreatic cancer tissues, peritoneal/pleural fluid and blood obtained so far. For the first four patients in which the autopsy was performed in <6 hours, we have successfully xenografted the primary tumor and/or two to four independent matched metastases from a variety of target organ sites, with a take rate of almost 60% for the first 26 xenografted tumors attempted. In an initial survey of KRAS2, TP53 and DPC4 genetic status in lethal metastatic pancreatic cancers, activating KRAS2 mutations were detected in 82% of cases and inactivating TP53 mutations in 55% of cases, consistent with rates of genetic alteration of these genes in early stage pancreatic cancers. However, DPC4 inactivation was found in 75% of patients analyzed, suggesting that genetic inactivation of the DPC4 tumor suppressor gene continues to be selected for with growth at the primary site and metastatic spread to other organs. The invaluable tissue resources generated by the success of the GICRMDP will provide an unparalleled resource for study of metastatic pancreatic cancer and of the metastatic process in general.

Figure 1

Establishment of xenografted tumors from metastatic pancreatic cancer tissues obtained at rapid autopsy. (A) Poorly differentiated pancreatic carcinoma metastatic to the lung (1.0 cm diameter) obtained from rapid autopsy of patient A2. (B) Xenografted tumor tissue A2.4 created from the identical metastatic pancreatic carcinoma shown in (A).

Figure 2

Dpc4 immunolabeling in metastatic pancreatic cancer. (A and B) Positive immunolabeling for Dpc4 is seen in both the primary carcinoma (A) and the matched liver metastasis (B) from patient A13. (C and D) In contrast, negative immunolabeling for Dpc4 is observed in the primary carcinoma (C) and the matched liver metastasis from patient A6 (D).