Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21 study, a phase III, randomized, placebo-controlled trial of erlotinib in patients with advanced NSCLC who had failed first-line or second-line chemotherapy, provided new treatment options for lung cancer. Given that only a small percentage of patients may benefit from treatment with inhibitors that target the EGF receptor (EGFR), substantial effort has been devoted to identifying biomarkers that are predictive of the highest likelihood of benefit from these drugs. Several markers, including EGFR tyrosine kinase domain mutation, EGFR gene copy number and KRAS mutation, have been investigated extensively, but results obtained to date remain controversial. This feature review discusses available data and the basis for the controversies.
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PMID:Predictive biomarkers for EGFR therapy. 1912 3

The purpose of the present study was to establish accurate prognostic markers to predict the post-operative recurrence of stage I lung adenocarcinomas (ADC). One-hundred and ninety cases of stage I ADC were examined for KRAS mutations and Ki-67 expression, and their associations with disease recurrence were analyzed. KRAS-mutated cases showed a significantly higher risk of recurrence than cases without mutations (5-year disease-free survival (DFS) 61.0% vs. 85.8%, P=0.017: adjusted Hazard ratio (HR) 4.55, 95% Confidence Interval (CI) 1.61-12.82, P=0.004). Ki-67 high-expressers (labeling index >10%) also showed a higher risk of recurrence than low-expressers (5-year DFS 68.7% vs. 93.2%, P<0.001: adjusted HR 3.84, 95% CI 1.18-12.45, P=0.025). Ki-67 high-expressers with KRAS mutations showed an additional higher risk of recurrence compared to low-expressers without mutations (5-year DFS 37.5% vs. 93.3%, P<0.001: adjusted HR 16.82, 95% CI 3.77-74.98, P<0.001) and their 5-year DFS was nearly equivalent to that of stage II non-small cell lung cancer (NSCLC) in our facility (37.5% vs. 37.2% for stage II NSCLC, p=0.577). The combined use of KRAS status and Ki-67 expression level could be an excellent prognostic marker to predict the post-operative recurrence of stage I ADC.
Lung Cancer 2009 Sep
PMID:Prognostic value of KRAS mutations and Ki-67 expression in stage I lung adenocarcinomas. 1916 66

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.
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PMID:LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. 1916 1

A subset of lung cancers harbors a small inversion within chromosome 2p, giving rise to a transforming fusion gene, EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene), which encodes an activated tyrosine kinase. We have earlier examined the presence of EML4-ALK by multiplex reverse transcription-polymerase chain reaction in 363 specimens of lung cancer, identifying 11 adenocarcinoma cases featuring the fusion gene. In this study, we clinicopathologically examined the characteristics of the EML4-ALK-positive cases, including the mutation status of EGFR, KRAS, and TP53, and whether they were of thyroid transcription factor-1 (TTF-1) cell lineage or not. Of 11 patients, 4 (36%) with EML4-ALK-positive lung adenocarcinomas who were below 50 years of age were affected by these diseases, as compared with 12 of 242 patients (5.0%) with EML4-ALK-negative lung adenocarcinomas (P=0.00038). EML4-ALK-positive lung adenocarcinomas were characterized by less-differentiated grade (P=0.0082) and acinar-predominant structure (P<0.0001) in histology. Furthermore, the presence of EML4-ALK appears to be mutually exclusive for EGFR and KRAS mutations (P=0.00018), whereas coexisting with TP53 mutations at a low frequency (1/11=9.1%), and correlating with non- or light smoking (P=0.040), in line with the TTF-1 immunoreactivity. Thus, EML4-ALK-positive tumors may form a distinct entity among lung adenocarcinomas, characterized by young onset, acinar histology, no or rare mutations in EGFR, KRAS, and TP53, and a TTF-1 cell lineage, all in agreement with the prevalence in non- or light smokers.
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PMID:EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. 1923 40

About 50% of patients presenting with resectable lung cancer develop distant metastases within 5 years. Genomic markers predicting metastatic behaviour of squamous cell lung carcinoma (SCC) are currently underexposed. We analyzed a cohort of patients with primary SCC using array-based comparative genomic hybridization (aCGH) to identify which genomic aberrations are related to metastatic behaviour. The cohort consisted of 34 patients with a follow-up of at least 5 years, 8 with metastases in regional lymph nodes only and 26 patients without any metastases at the time of surgery. Eleven of the latter 26 developed metastases in distant organs within 3 years after surgery. Copy number changes observed in at least 40% of all SCC included gains at chromosomal arms 3q, 5p, 8q, 19q, 20p, 22q and losses at 3p, 4p, 4q, 5q, 8p and 9p. High copy number amplifications were observed at 2p15-p16, 3q24-q29, 8p11-p12, 8q23-q24, and 12p12, containing candidate oncogenes such as BCL11A, REL, ECT2, PIK3CA, ADAM9, MYC and KRAS. Amplification of 2p15-p16 is a novel finding in SCC. Another novel finding is the homozygous deletion observed at 4q33-34.1 in 15% of the SCC cases. Gains at 7q36, 8p12, 10q22, 12p12, loss at 4p14 and the homozygous deletions at 4q occurred significantly more frequent in SCC from patients with lymph node metastases only. SCC from patients with distant metastases showed a significantly higher gain frequency at 8q22-q24 and loss at 8p23 and 13q21, and a significantly lower gain frequency at 2p12 and 2p16 and loss at 11q25 compared with SCC from patients without metastases. Of these, gains at 7q, 8p and 10q were restricted to SCC with lymph node metastasis and gain at 8q was restricted to patients with distant metastasis. Two genomic aberrations, i.e. loss of 4p and gain of 19q12 were observed more frequently in SCC with only lymph node metastases as compared to SCC with distant metastases. In conclusion, we identified genomic aberrations in primary SCC that were related to lymph node or distant metastases.
Lung Cancer 2009 Dec
PMID:Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. 1932 46

Some non-small cell lung cancers (NSCLCs) harbor a single specific mutated oncogene that is thought to be the primary genetic "driver" leading to cancer. The two most commonly mutated oncogenes in lung cancer encode for the epidermal growth factor receptor (EGFR) and KRAS. EGFR kinase domain mutations were only recently identified, but they have already been established in the clinic as valid predictors of increased sensitivity to EGFR kinase inhibitors (gefitinib and erlotinib). By contrast, even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC. In this review, we summarize the initial discovery of RAS mutations in NSCLC, describe work exploring associations with clinical factors and outcomes, and provide an overview of current approaches to targeting KRAS mutant NSCLC.
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PMID:KRAS mutations in non-small cell lung cancer. 1934 89

The paxillin gene (PXN) encodes a focal adhesion associated protein that could be involved in the progression of lung cancer through its interactions with the actin cytoskeleton and key signal transduction oncogenes. PXN mutations and PXN amplifications were recently identified in nonsmall-cell lung cancer (NSCLC) and amplifications were associated with MET increased copy number. The description of tumors with two to three mutations in the PXN gene and the overrepresentation of GC to AT transitions were unexpected and needed confirmation. The aim of this study was to validate the incidence of PXN somatic alterations in NSCLC and to correlate them to other common genetic alterations. PXN mutations and copy number changes at PXN, EGFR, and MET loci were analyzed on DNAs from frozen tumor samples (n = 159) that had been previously screened for mutations at EGFR, KRAS, BRAF, ERBB2, STK11, PIK3CA, and TP53. We found PXN polymorphisms including nonsynonymous ones but no PXN amplification and only 1/159 (<1%) somatic tumor mutation F416L. In conclusion, we do not deny the possible involvement of PXN in cancer but our findings do not support a major role for PXN somatic changes in lung carcinogenesis.
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PMID:No somatic genetic change in the paxillin gene in nonsmall-cell lung cancer. 1935 96

The present study investigated the potential difference between EGFR-mutated lung adenocarcinoma (ADC) and KRAS-mutated ADC in relation to past illness and family history. Among the 153 tumors examined, 33 (21.6%) were EGFR-mutated, and 22 (14.4%) were KRAS-mutated. The EGFR-mutated cases showed a significantly higher prevalence of past illness involving the gastric cancer in males (EGFR 3/8 (37.5%), KRAS 0/13 (0.0%), no mutation (NONE) 1/57 (1.8%); Fisher's exact test, P=0.0064) or uterine myoma in females (EGFR 8/25 (32.0%), KRAS 0/9 (0.0%), NONE 3/41 (7.3%); Fisher's exact test, P=0.0139). No association between the mutations and family history was found. The EGFR-mutated ADC is therefore likely to develop through a distinct carcinogenetic pathway from the others, but genetic backgrounds seemed unlikely to be determinant predisposing to the EGFR-mutated ADC.
Lung Cancer 2009 Dec
PMID:Significant association between EGFR-mutated lung adenocarcinoma and past illness from gastric cancer or uterine myoma: its implication in carcinogenesis. 1936 47

MicroRNA (miRNA)-binding site polymorphisms that could contribute to disease risk and prognosis are rapidly being identified and investigated as this genetic variation may have a potentially profound impact on human health. A recently described variant allele in the KRAS 3' untranslated region that arises in the let-7 miRNA complementary site (KRAS-LCS6) and leads to increased KRAS expression in lung cancer was examined for its association with the occurrence of head and neck squamous cell carcinoma (HNSCC). We examined the prevalence of the KRAS-LCS6 variant allele in a population-based case-control study of HNSCC to determine if this KRAS-LCS6 genotype was associated with disease occurrence and patient survival. Although the KRAS-LCS6 variant genotype was not associated with the overall risk of HNSCC, cases with the KRAS-LCS6 variant genotype had significantly reduced survival [hazard ratio (HR), 1.6; 95% confidence interval (CI), 1.0-2.5] in models controlled for confounders of survival. This risk was greatest in cases of oral cavity carcinoma (HR, 2.7; 95% CI, 1.4-5.3). These data demonstrate that cases with the KRAS-LCS6 variant have significantly reduced survival time and suggest that this variant may alter the phenotype or therapeutic response of this disease.
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PMID:A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers. 1938 May 22

Aberrant proteins encoded from genes altered in tumors drive cancer development and may also be therapeutic targets. Here we derived a comprehensive gene-alteration profile of lung cancer cell lines. We tested 17 genes in a panel of 88 lung cancer cell lines and found the rates of alteration to be higher than previously thought. Nearly all cells feature inactivation at TP53 and CDKN2A or RB1, whereas BRAF, MET, ERBB2, and NRAS alterations were infrequent. A preferential accumulation of alterations among histopathological types and a mutually exclusive occurrence of alterations of CDKN2A and RB1 as well as of KRAS, epidermal growth factor receptor (EGFR), NRAS, and ERBB2 were seen. Moreover, in non-small-cell lung cancer (NSCLC), concomitant activation of signal transduction pathways known to converge in mammalian target of rapamycin (mTOR) was common. Cells with single activation of ERBB2, PTEN, or MET signaling showed greater sensitivity to cell-growth inhibition induced by erlotinib, LY294002, and PHA665752, respectively, than did cells featuring simultaneous activation of these pathways, underlining the need for combined therapeutic strategies in targeted cancer treatments. In conclusion, our gene-alteration landscape of lung cancer cell lines provides insights into how gene alterations accumulate and biological pathways interact in cancer.
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PMID:A gene-alteration profile of human lung cancer cell lines. 1947 7


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