Bioinformatics of Non Small Cell Lung Cancer and the Ras Proto-Oncogene

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The resulting prognostic clusters showed largely consistent clinical categorizations in both entities. This suggests mutant subtype-specific functional properties leading to similar clinical effects.

Our findings provide a framework for risk stratification of specific RAS mutations across several cancer entities, which is required to guide the analysis of clinical findings in patients treated with direct RAS inhibitors or agents targeting downstream pathways. RAS proteins and their regulators in human disease. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol Cancer Res. Biological properties of human c-Ha-ras1 genes mutated at codon K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression.

Cancer Res. KRAS p.

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G13D mutations are associated with sensitivity to anti-EGFR antibody treatment in colorectal cancer cell lines. J Cancer Res Clin Oncol. Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state.

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Cancer Discov. Oncol Lett. Comprehensive molecular profiling of lung adenocarcinoma. A comprehensive survey of Ras mutations in cancer. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med.

Tracking the evolution of non—small-cell lung cancer. N Engl J Med. Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection. Sci Rep. Haigis KM. KRAS alleles: the devil is in the detail. Trends Cancer. Somatic mutations affect key pathways in lung adenocarcinoma. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing.

Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. Comprehensive genomic characterization of squamous cell lung cancers. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.

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J Clin Oncol. Prognostic survival associated with left-sided vs right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol.

Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Is right-sided colon cancer different to left-sided colorectal cancer? Eur J Surg Oncol. Lans H, Vermeulen W. Tissue specific response to DNA damage: C. DNA Repair Amst. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell. Iyama T, Wilson DM.

DNA repair mechanisms in dividing and non-dividing cells. DNA damage in stem cells. Mol Cell. Consistent with previously reported studies [ 9 — 16 ], the major differences in copy number and gene expression profiles between AC and SCC of the lung involved chromosome 3q. The strong independent correlation with amplification and over-expression at this locus suggests a causal relationship in SCC for genes in this region which warrant further investigation.

These include TP73L , a gene extensively implicated in SCC, whose expression was most strongly correlated with the SCC phenotype, and which has been previously reported to be a putative oncogene [ 22 — 32 ]. Recently published clinical data [ 35 ] suggest there are histotype-specific differences in response to systemic therapies. Validation of the differential activity of the roles of these genes and sensitivity to conventional and novel chemotherapeutic agents may be an area for future research. However, we also observed a correlation between 3q amplification and TP53 mutations in AC samples.

This suggests that the apparent association between TP53 mutations and SCC may be mediated by the relationship between TP53 mutations and amplification of regions of 3q.

Tumours possessing mutations of KRAS express genes playing key roles in cell growth, chromosome organisation and gene regulation. The gene expression profile observed in 'metastatic' tumours is consistent with a growing body of literature implicating deregulated protein synthesis in the development and metastatic potential of human cancers [ 44 , 45 ]. Increased mRNA translation is a critical downstream function of many cancer related genes, and many gene products with roles in metastasis are not mutated but inappropriately expressed in malignant cells e. Opportunities for therapeutic intervention currently in development include oncolytic viruses that require deregulated protein translation for their replication [ 18 ], or agents that inhibit mTOR, an integral factor in protein translation eg.

While the small number of recurrences and deaths due to NSCLC in our tumour-set makes it difficult to draw strong conclusions, transcriptional profiles linked to tumour recurrence suggest KRAS pathway activation. SCC in the 'recurrent' group. Importantly, our prognostic gene signature was validated in an independent test set, suggesting that these findings may eventually yield prognostic markers in resected early-stage NSCLC to better select patients for adjuvant treatments. Although the size of the current study is small, our findings are in many cases consistent with those of previous studies, and have been validated in the case of the prognostic classifier in an independent test set.

In addition, several novel molecular changes associated with clinically relevant endpoints have been demonstrated. It is hoped that these results will contribute to identifying new predictive markers and targets for novel therapies to improve treatment selection and better outcomes for patients with this deadly disease. American Journal of Pathology. Weiss MM, et al: Genomic alterations in primary gastric adenocarcinomas correlate with clinicopathological characteristics and survival. Cell Oncol. Krypuy M, et al: High resolution melting for mutation scanning of TP53 exons BMC Cancer.

Krypuy M, et al: High resolution melting analysis for the rapid and sensitive detection of mutations in clinical samples: KRAS codon 12 and 13 mutations in non-small cell lung cancer. Smyth G: Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Statistical applications in genetics and molecular biology. Smyth G, et al: The use of with-in array replicate spots for assessing expression in microarray experiments.

Petersen I, et al: Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res. Bjorkqvist A, et al: DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes Chromosomes Cancer. Pei J, et al: Genomic imbalances in human lung adenocarcinomas and squamous cell carcinomas. Massion P, et al: Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridisation: implications of the phosphatidylinositol 3-kinase pathway.

Kim T, et al: Genome-wide screening of genomic alterations and their clinicopathologic implications in non-small cell lung cancers. Clin Cancer Res. Tonon G, et al: High-resolution genomic profiles of human lung cancer. Garnis C, et al: High resolution analysis of non-small cell lung cancer cell lines by whole genome tiling path array CGH. Int J Cancer.

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Human Pathology. The journal of biological chemistry. Glickman J, et al: Expression of prelated protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders. Di Como C, et al: p63 expression profiles in human normal and tumour tissues. Pruneri G, et al: p63 in laryngeal squamous cell carcinoma: evidence for a role of TA-p63 down-regulation in tumorigenesis and lack of prognostic implications of p63 immunoreactivity.

Lab Invest. Massion P, et al: Significance of p63 amplification and overexpression in lung cancer development and prognosis. Au N, et al: P63 expression in lung carcinoma: a tissue microarray study of cases. Appl Immunohistochem Mol Morphol. J Clin Pathol. Thurfjell N, et al: Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck.

Int J Oncol. Nylander K, et al: Differential expression of p63 isoforms in normal tissues and neoplastic cells. J Pathol. De Young MP, et al: Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma. Ebert E, et al: Expression of cysteine protease inhibitors stefin A, stefin B, and cystatin C in human lung tumor tissue. Adv Exp Med Biol. Werle B, et al: Cystatins in non-small cell lung cancer: tissue levels, localization and relation to prognosis.

Oncol Rep. Scagliotti GV, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. Takahashi T, et al: p a frequent target for genetic abnormalities in lung cancer. Cancer - principles and practice of oncology. Pao W, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PloS Med. Peeters M, et al: Association of progression-free survival, overall survival, and patient-reported outcomes by skin toxicity and KRAS status in patients receiving panitumumab monotherapy.

Bokemeyer C, et al: Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.

Identification of candidate genes for lung cancer somatic mutation test kits

J Neurobiol. Biochem Biophys Res Commun. Ramaswamy S, et al: A molecular signature of metastasis in primary solid tumours. Nature Genetics. Weigelt B, et al: Gene expression profiles of primary breast tumours maintained in distant metastases. J Biol Chem. Cancer Sci. Download references. Correspondence to Genni M Newnham. AD performed and supervised mutation analyses. HD performed mutational analyses. JL and NT performed statistical analysis. KO performed pathology review. DT and MC conceived the idea of the study.

DT supervised molecular studies and assisted in the preparation of the manuscript. All authors read and approved the final copy of the manuscript. This article is published under license to BioMed Central Ltd. Reprints and Permissions. Search all BMC articles Search. Abstract Background The aim of this study was to identify critical genes involved in non-small cell lung cancer NSCLC pathogenesis that may lead to a more complete understanding of this disease and identify novel molecular targets for use in the development of more effective therapies.