Oncogenes in lung cancer

There are a series of morphologically distinct changes that occur in the bronchial epithelium before the appearance of a clinically overt lung tumour including hyperplasia, dysplasia and carcinoma in situ. A number of mutations in onco-genes have been associated with these early stages as well as with the cancers themselves and may be of use as diagnostic or prognostic tools. Lung cancers can be divided broadly into two groups - the small-cell lung cancers (SCLCs) and the non-small-cell lung cancers (NSCLCs). The latter group can be subdivided into adenocarcinomas, squamous cell carcinomas (SQCs) and large-cell carcinomas with different genes being associated with each group.

Over-expression of the growth factor receptor group of oncogenes is a common abnormality in lung cancers. Over-expression of EGFR is consistently seen, primarily in NSCLCs of the SQC type. One study showed that over-expression was not associated with a survival difference (Rusch et al., 1995) but suggested that this growth factor/receptor loop was more important for lung tumour formation than for tumour progression. However, others have found an association between over-expression of the receptor and poor prognosis (Brabender et al., 2001; Pastorino et al., 1997). HER2 amplification is seen in approximately a third of NSCLC, particularly adenocarcinomas, and over-expression has been correlated with shorter survival (Brabender et al., 2001; Han et al., 2002). Given these findings prospective studies on the use of the anti-HER2 monoclonal antibody, Herceptin, are underway (Hirsch et al., 2002). The KIT oncogene has been shown to be expressed in over 70% of SCLCs and has been suggested as a possible target for therapy with the tyrosine kinase inhibitor STI571 (Heinrich et al., 2002). MET as been shown to be consistently activated in lung cancers where it is believed to contribute to tumour progression.

RAS mutations are found in 30% of NSCLCs especially in adenocarcinomas, though RAS is rarely mutated in SCLCs (Mao et al., 1994). Mutations occur primarily in KRAS and mutations at codon 12 are those most frequently found. Most mutations are G to T transversions which may be a reflection of DNA damage by nitrosamines in cigarette smoke (Ahrendt et al., 2001). KRAS mutations were initially believed to be poor prognostic indicators, but more recent studies have not upheld this observation (Niklinski et al., 2001). However, a combination of KRAS mutations plus alterations in other markers such as p53 and ERBB2 have been demonstrated to have an improved prognostic value (Schneider et al., 2000).

Of all the characterised members of the MYC family of genes, only MYC gene amplification or over-expression due to transcriptional deregulation is common to both NSCLC and SCLC, whereas abnormalities of two others, MYCN and MYCL, are specifically associated with SCLC. In general, abnormalities of MYC are associated with an adverse outcome. MYC deregulation has been found in preneoplastic lesions associated with NSCLCs suggesting an early role for MYC in lung cancer development (Broers et al., 1993).

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