Personalized chemotherapy profiling using cancer cell lines from selectable mice.

Purpose: High-throughput chemosensitivity testing of low-passage cancer cell lines can be used to prioritize agents for personalized chemotherapy. However, generating cell lines from primary cancers is difficult because contaminating stromal cells overgrow the malignant cells.

Experimental Design: We produced a series of hypoxanthine phosphoribosyl transferase (hprt)-null immunodeficient mice.

Distant metastasis occurs late during the genetic evolution of pancreatic cancer.

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known.

Quantifying the relative amount of mouse and human DNA in cancer xenografts using species-specific variation in gene length.

Human cancer cell lines and xenografts are valuable samples for whole-genome sequencing of human cancer. Tumors can be maintained by serial xenografting in athymic (nude) or severe combined immunodeficient (SCID) mice. In the current study, we developed a molecular assay to quantify the relative contributions of human and mouse in mixed DNA samples.

In vivo and in vitro propagation of intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are one of the three known curable precursor lesions of invasive pancreatic ductal adenocarcinoma, an almost uniformly fatal disease. Cell lines from IPMNs and their invasive counterparts should be valuable to identify gene mutations critical to IPMN carcinogenesis, and permit high-throughput screening to identify drugs that cause regression of these lesions. To advance the study of the biological features of IPMNs, we attempted in vivo and in vitro growth of selected IPMNs based on the hypothesis that IPMNs could be grown in the most severely immunodeficient mice.

Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.

Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2.

Absence of germline BRCA1 mutations in familial pancreatic cancer patients.

Recent studies have suggested that germ line mutations in the BRCA1 gene may confer an increased risk of developing pancreatic cancer. To determine if BRCA1 mutations explain a significant proportion of familial pancreatic cancer, we sequenced the BRCA1 gene in a large series of well-characterized patients with familial pancreatic cancer and we evaluated the pathology of breast neoplasms that developed in relatives of pancreatic cancer patients. The BRCA1 gene was fully sequenced in 66 pancreatic cancer patients enrolled in the National Familial Pancreas Tumor Registry who had at least two additional relatives with pancreatic cancer.

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.

There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples.