Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer

Abstract

Purpose: 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.

Experimental design: 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.

Figure 1

Overview of the experimental approach.

Figure 2

Copy number alterations in case 7. A–D, the top, middle, and bottom are the allele ratio, the copy number, and the allele-specific ratio, respectively. Each red and blue dot in the bottom represent allele, and the dots are displayed on the panel to indicate the ratio of each allele. A–D, PanIN-2. A, chromosome 6 (one allele of most of 6q is absent); B, chromosome 14 (incomplete loss of the chromosome); C, chromosome 16 (gain of most of 16q); and D, chromosome 17 (loss of all of 17p and most of 17q).

Figure 3

Copy number alterations of chromosome 9 in case 11. A and B, the top, middle, and bottom are the allele ratio, the copy number, and the allele-specific ratio, respectively. Each red and blue dot in the bottom represent allele, and the dots are displayed on the panel to indicate the ratio of each allele. Experimental replicates of case 11 showed identical chromosome 9p21.3 band loss covering CDKN2A/p16 loci. A, PanIN-2 and B, PanIN-2 sampled from near the lesion in A.