Pancreatic Cancer molecular biology and genetics

The molecular stages in the development and progression of pancreatic cancer are not fully understood but some of the key genetic alterations have been identified 8.

Many of these changes disturb normal cell cycle regulation and promote growth of cancer cells. Some of the earliest genetic alterations observed in cancer progression occur in the proto-oncogene, K-RAS. Mutations in K-RAS become more common as cancer progresses and are reported in almost 100% of cases. Genes that are thought to influence the later stages of disease progression include CDKN2A (which encodes two  tumour suppressors, ARF and INK4A), TP53 and DPC4/SMAD4. Faults in CDKN2A have been reported in 80-95% of cases, while faults in TP53 occur in around 50% of cases. Changes in TP53 are commonly missense mutations in the DNA binding domain. Loss of TP53 is associated with aneuploidy (having one or more chromosomes above or below the normal chromosome number), which is common in pancreatic cancer. Deletion of 18q21 containing the DPC4/SMAD4 gene occurs in around 30% of pancreatic cancers and is a marker for poor clinical outcome.

Around 10% of cases of pancreatic cancer are associated with an inherited faulty gene. A small proportion of these cases are linked to cancer syndromes that increase the risk of the disease 8,9. In a European study of 26 families with at least two first-degree relatives with pancreatic cancer, 19% of cases were found to be due to mutations in the BRCA2 gene 10. Inherited mutations in BRCA2 increase the risk of pancreatic cancer, but this risk is lower than that of developing breast and ovarian cancer. In sporadic cancers, BRCA2 mutations are observed in up to 10% of cases and are thought to occur late in tumour development 8,11.

A number of other cancer syndromes also carry an increased risk of pancreatic cancer, including Peutz-Jeghers ( LKB1/STK11), Lynch syndrome, (mutations in mismatch repair genes) and familial atypical multiple mole syndrome, or FAMM ( CDKN2A). Unusually, pancreatic cancer linked to these syndromes does not have an early onset but occurs at a similar age to sporadic cases. Pancreatic cancer can occur as a feature of other inherited diseases including hereditary pancreatitis, cystic fibrosis and ataxia-telangiectasia 9.

The majority of familial cases are not associated with a cancer syndrome or other inherited disease. Of these, many families exhibit an autosomal dominant pattern of inheritance and the susceptibility gene in one large USA pedigree has been localised to chromosome 4q32-34 12, although the gene itself has not been identified.

Progress in diagnosis and treatment will benefit from the results of large-scale genome analysis using microarrays to identify prognostic markers and possible drug targets. For example, high levels of the calcium binding protein, calcyclin, are associated with poor survival 13. Reduced levels of the protein BNIP3, from the Bcl-2 family, have been observed in 90% of cancer tissue samples and could provide a useful marker of sensitivity to the drug gemcitabine 14.