K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review

Abstract

Multiple genomic alterations are involved in the development of most human cancers. They include alterations in oncogenes, tumor suppressor genes, DNA mismatch repair and excision repair genes. Genetic testing for susceptibility has been a part of the management of patients with well-defined but uncommon hereditary cancers in which certain susceptible gene mutations are determined in the germ line. However, a molecular diagnostic approach to sporadic cancers, which comprise the vast majority of malignant tumors in human beings, is still under development. One of the best characterized tumor-related genes is K-ras, which somatically mutates in several types of sporadic human cancers. Since mutations of this gene occur exclusively in three hot spots (codons 12, 13 and 61), and are frequently detected and well characterized in colorectal, pancreas and lung cancers, molecular diagnosis and susceptibility (risk) assessment targeting K-ras mutations are being developed. For this purpose, sample collection methods that reflect the state of the entire affected organ are important. Clinical samples used for molecular diagnosis and risk assessment include stool and lavage fluid, pancreatic and duodenal juices, and sputum and lavage fluids for colorectal, pancreas and lung cancers, respectively. The reported incidence of K-ras mutations detected in these samples ranges from 7% to 80% for colorectal cancers, 25% to 87% for pancreatic cancers, and 25% to 48% for lung cancers. Incidence of mutations clearly depends on the sensitivity of the method for detecting the mutant K-ras allele, as well as the nature and the quality of the clinical samples. Various methods including plaque hybridization, dot blot hybridization, combined PCR and RFLP or SSCP, and sensitive PCR have been used, and they exhibited high specificity (75 to 100%) in detecting mutations. Molecular analysis is demonstrating promise in assessing susceptibility to, or risk of developing, sporadic cancers.