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Research Paper
Copy-Number Variants in Patients with a Strong Family History of Pancreatic Cancer
Robert Lucito, Shubha Suresh, Kimberly Walter, Akhilesh Pandey, B. Lakshmi, Alex Krasnitz, Jonathan Sebat, Michael Wigler, Alison P. Klein, Kieran Brune, Emily Palmisano, Anirban Maitra, Michael Goggins and Ralph H. Hruban
volume 6 | issue 10
October 2007Pages: 1592 - 1599
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Copy-number variants such as germ-line deletions and amplifications are associated with inherited genetic disorders including familial cancer. The gene or genes responsible for the majority of familial clustering of pancreatic cancer have not been identified. We used representational oligonucleotide microarray analysis (ROMA) to characterize germ-line copy number variants in 60 cancer patients from 57 familial pancreatic cancer kindreds. Fifty-seven of the 60 patients had pancreatic cancer and three had non-pancreatic cancers (breast, ovary, ovary). A familial pancreatic cancer kindred was defined as a kindred in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Copy-number variants identified in 607 individuals without pancreatic cancer were excluded from further analysis. A total of 56 unique genomic regions with copy-number variants not present in controls were identified, including 31 amplifications and 25 deletions. Two deleted regions were observed in two different patients, and one in three patients. The germ-line amplifications had a mean size of 662Kb, a median size of 379Kb (range 8.2Kb to 2.5Mb) and included 425 known genes. Examples of genes included in the germ-line amplifications include the MAFK, JunD and BIRC6 genes. The germ-line deletions had a mean size of 375Kb, a median size 151Kb (range 0.4Kb to 2.3Mb) and included 81 known genes. In multivariate analysis controlling for region size, deletions were 90% less likely to involve a gene than were duplications (p<0.01). Examples of genes included in the germ-line deletions include the FHIT, PDZRN3 and ANKRD3 genes. Selected deletions and amplifications were confirmed using real-time PCR, including a germ-line amplification on chromosome 19. These genetic copy-number variants define potential candidate loci for the familial pancreatic cancer gene.