BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications - PubMed (original) (raw)
BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications
M Goggins et al. Am J Pathol. 2000 May.
Abstract
Patients harboring germline BRCA2 mutations are at an increased risk of developing pancreatic cancer. We investigated the prevalence of biallelic inactivation of BRCA2 in the presumed precursors to invasive pancreatic ductal carcinomas, pancreatic intraepithelial neoplasia (PanIN). Surgical resection specimens from three patients with germline BRCA2 mutations who developed pancreatic ductal adenocarcinoma were studied. Fourteen PanINs were needle-microdissected from paraffin-embedded tissue. DNA was isolated from these microdissected tissues and amplified by primer-mediated pre-amplification. Loss of heterozygosity at the BRCA2 locus was determined by polymerase chain reaction amplification and cycle sequencing. The presence of the wild-type alleles was evaluated at the nucleotide positions of the germline BRCA2 mutations. The K-ras gene was sequenced at codon 12 and 13 to confirm the efficacy of microdissection. By histological evaluation the prevalence of PanINs in these patients was not notably elevated. Loss of the wild-type allele of BRCA2 was present in one high-grade PanIN (PanIN 3), but in none of 13 low-grade PanINs (PanIN 1). In contrast, K-ras mutations were detectable in 7 of the 14 PanINs. These results suggest that biallelic inactivation of the BRCA2 gene is a relatively late event in pancreatic tumorigenesis. In contrast to classical molecular progression models of tumorigenesis, the inactivation of the wild-type allele in a carrier of a recessive tumor susceptibility gene may not always be the first somatic event during the molecular evolution of a cancer. The necessity for earlier genetic alterations before biallelic inactivation of a recessive tumor susceptibility gene such as BRCA2 may explain why affected carriers have normal numbers of neoplastic precursor lesions, a relatively low phenotypic penetrance, and late age of onset of pancreatic and other cancers.
Figures
Figure 1.
Sequence of the BRCA2 gene upstream of the 2481insT germline mutation in two PanIN lesions from a patient with pancreas cancer (case PX101). The first duct lesion (lane pair 1, PanIN-3) shows the mutant sequence with loss of the wild-type BRCA2 sequence, whereas the second lesion (lane pair 2, PanIN-1) shows the sequence of both the wild-type and mutant alleles (note the double bands for each nucleotide, best seen on comparison of the T lanes). G and T refer to deoxyguanosine and deoxythymidine termination reactions, respectively.
Figure 2.
A: The PanIN-3 duct lesion that harbored LOH of the wild-type BRCA2 gene. B: An example of a PanIN-1 duct lesion from patient PX66 that did not have LOH at BRCA2. Hematoxylin and eosin; original magnification, ×40.
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