Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer.
OBJECTIVE
Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes.


METHODS
We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations.


RESULTS
Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (∼95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p.


CONCLUSIONS
Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Seung-Mo
SM
Hong
Audrey
A
Vincent
Mitsuro
M
Kanda
Julie
J
Leclerc
Noriyuki
N
Omura
Michael
M
Borges
Alison P
AP
Klein
Marcia Irene
MI
Canto
Ralph H
RH
Hruban
Michael
M
Goggins
D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D011905:Genes, ras; D055106:Genome-Wide Association Study; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*