Molecular Pathology

K-ras Oncogene

Oncogenes can be activated through various mechanisms, including a point mutation within a gene and amplification of the gene itself. Activating point mutations in codon 12 of the K-ras oncogene are among the most common genetic alterations identified to date in IDC [23]. These mutations can be found in 80-95% of PCs [24]. Activating point mutations in the K-ras gene occur early in the development of a pancreatic neoplasia before an invasive cancer develops. Therefore, detection of a point mutation in the K-ras gene has the potential to detect curable, non-invasive pancreatic neoplasia before it progresses to incurable invasive cancer [25]. However, K-ras mutations are so common in normal, hyperplastic, metaplastic, and neoplastic ductal cells that this mutation may not cause, but only promote, mucinous differentiation. The prevalence of a certain mutation pattern in non-neoplastic and neoplastic ductal cells in an individual pancreas suggests the dominance of one of the carcinogenic factors [26].

Tumor-Suppressor Genes

In sporadic cancers, tumor-suppressor genes can be inactivated by (1) an intragenic mutation in one allele coupled with loss of the second allele, (2) deletion of both alleles (homozygous deletion), or (3) hypermethylation of the promoter of the gene associated with silencing of gene expression. In familiar cancers with germline mutations of one allele, the tumor suppressor gene can be inactivated by loss of the second allele.

The p16 gene on chromosome 9p is inactivated in 40% of pancreatic cancers by homozygous deletion, in another 40% by an intragenic mutation in one allele coupled with the second allele, and in 15% by silencing associated with hypermethylation of the gene's promoter [27]. The p16 functions are to regulate the cell cycle through the 16/Rb pathway. The inactivation of the p16 gene in almost all PCs means that a critical regulator of the cell cycle is lost.

The p53 tumor-suppressor gene on chromosome 17p is inactivated in 55-75% of PCs, almost always by an intragenic mutation in one allele coupled with loss of the second allele [28]. The p53 protein regulates the G1/S cell cycle checkpoint, maintenance of G2/M arrest, and the induction of apoptosis. The loss of p53 means loss of cell division and cell death in the majority of PCs.

The Smad4 (DPC4) gene on chromosome 18q is inactivated in 55% of PCs; in 35% by homozygous deletion and in 20% by an intragenic mutation coupled with loss of the remaining allele [29]. Smad4 plays a critical role in signaling through the transforming growth factor type B (TGF-P) pathway. The TGF-P pathway is activated by the TGF-P protein's binding to specific surface receptors. This triggers an intracellular cascade and results in the nuclear location of Smad4. Once in the nucleus, Smad4 has growth-controlling effects by regulating the expression of specific target genes.

Mismatch Repair Genes

Genome-maintenance genes repair damage to DNA. When a genome-maintenance gene is inactivated, DNA damage is not repaired efficiently and DNA mutations accumulate. Mutations occurring in cancer-associated genes can contribute to tumorigenesis.

The DNA mismatch repair genes MLH1 and MSH2 are examples of genome-maintenance genes targeted in pancreatic cancer [30, 31]. When one of these genes is inactivated, either by mutation or promoter hypermethylation, mutations accumulate in these repetitive tracts, producing DNA changes called microsatellite instability. Approximately 4% of pancreatic cancers have microsatellite instability and these cancers show a specific histology as poorly differentiated medullary carcinomas [30, 31].

The BRCA2 gene on chromosome 13q is also a genome-maintenance gene and it is targeted in a small percentage of PCs (< 10%) [32]. However, germline (inherited) mutation in BRCA2 can cause the familial aggregation of PC, and carriers of this mutation have a 10-fold increased risk of developing PC, as well as an increased risk of developing breast, prostate, and ovarian cancers [33].

Telomere Shortening

Telomeres are caps at the ends of chromosomes that normally function to protect the terminal sequences and prevent the ends of chromosomes from joining aberrantly [34]. Telomeres are composed of short repeated DNA sequences and associated proteins. It appears that telomeres become abnormally short very early in the development of pancreatic neoplasia, in the non-invasive PanIN stage [35]. These shortened telomeres can presumably lead to the abnormal fusion of chromosome ends and ultimately to chromosome instability, promoting further neoplastic progression in these cells. When cells with critically short telomeres divide, the abnormally fused chromosomes will break, resulting in the gain of genetic material by some daughter cells and the loss of genetic material in other daughter cells. This process, called a breakage-fusion-bridge cycle, has been observed in PCs and is believed to be one of the major causes for the loss of tumor-suppressor genes and the gain of oncogenes.

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