K-ras mutation: Early detection in molecular diagnosis and risk assessmentof colorectal, pancreas, and lung cancers - A review

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 susceptibil ity has been a part of the management of patients with well-defined but unc ommon hereditary cancers in which certain susceptible gene mutations are de termined in the germ line. However, a molecular diagnostic approach to spor adic cancers, which comprise the vast majority of malignant tumors in human beings, is still under development. One of the best characterized tumor-re lated genes is K-ras, which somatically mutates in several types of sporadi c human cancers. Since mutations of this gene occur exclusively in three ho t spots (codons 12, 13 and 61), and are frequently detected and well charac terized in colorectal, pancreas and lung cancers, molecular diagnosis and s usceptibility (risk) assessment targeting K-ras mutations are being develop ed. For this purpose, sample collection methods that reflect the state of t he entire affected organ are important. Clinical samples used for molecular diagnosis and risk assessment include stool and lavage fluid, pancreatic a nd duodenal juices, and sputum and lavage fluids for colorectal, pancreas a nd lung cancers, respectively. The reported incidence of K-l-as mutations d etected 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 o f 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 clini cal samples, Various methods including plaque hybridization, dot blot hybri dization, combined PCR and RFLP or SSCP, and sensitive PCR have been used, and they exhibited high specificity (75 to 100 %) in detecting mutations. M olecular analysis is demonstrating promise in assessing susceptibility to, or risk of developing, sporadic cancers.