Topographic analysis of K-ras mutations in histologically normal lung tissues and tumours of lung cancer patients

Abstract

Mutations in the K-ras gene are very common in lung tumours and are implicated in the development of lung cancer, but the timing of their occurrence remains poorly understood. We investigated K-ras mutations in cell samples microdissected by laser capture microscopy at multiple sites from lung tissue sections representing tumour tissue and matched histologically normal tissue obtained from 48 lung cancer patients. K-ras mutations were detected in cell samples from 10 of 38 (26.3%) lung adenocarcinomas and in none of the histologically normal or tumour cell samples taken from 10 lung squamous cell carcinomas. Of the K-ras mutation-positive adenocarcinomas, in 4 cases a mutation was found in only the tumour tissue, in 1 case a mutation was found only in the histologically normal tissue, and in 5 cases mutations were found in both the tumour tissue and histologically normal tissue. Among these 5 cases, 2 had identical mutations in both the tumour tissue and histologically normal tissue, 2 had 1 mutation in the tumour tissue and 2 mutations in the histologically normal tissue, 1 of which was identical to the mutation found in the tumour, and 1 case had 2 codon 12 mutations in tumour tissue and 2 mutations, in codons 9 and 11, in histologically normal tissue. These results showed that K-ras mutations are frequent in histologically normal cells taken from outside lung adenocarcinomas and suggest that some of these mutations may represent early events which could pave the way of lung carcinogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.com

Mutations in K-ras Codon 12 Detected in Plasma DNA Are Not an Indicator of Disease in Patients with Non-Small Cell Lung Cancer

“…Because chronic inflammation may be present in patients without cancer as well as those with cancer (9 ), the analysis of K-ras mutations in plasma may be influenced by such factors. Finally, as reported recently by Keohavong et al (10 ), K-ras mutations are frequently found in histologically normal tissues near tumors, suggesting that such mutations may represent an early event in the development of lung cancer. K-ras mutations thus may be present before clinically detectable tumors.…”

Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

“…These findings have other important clinical implications. They also suggest that the use of RAF inhibitors might be pointless and even deleterious in normal tissues especially in cells harboring a RAS mutation, as it can be found in lung and colon tissue, for example (40,41). Indeed, we cannot exclude the hypothesis that RAF inhibitors could promote cell transformation and/or proliferation in these wtBRAF cells with RAS activation and lead to internal tumors.…”

Low-Frequency Kras Mutations are Prevalent in Lung Adenocarcinomas

“…Thus, it is possible that KRAS codon 12 GAT mutant cells within a tumor appear normal. The fact that KRAS codon 12 mutations have been observed frequently in normal tumor adjacent epithelia, which may or may not be the same KRAS mutation present in the lung adenocarcinoma cells, may provide additional support for this idea [60]. If true, this has clinical significance, because analyzing microdissected tumor samples by DNA sequencing (rather than considering a larger tumor sample using a high-sensitivity method) could potentially decrease the likelihood of KRAS mutation detection in clinical samples.…”