Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer: the EUELC cohort

Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53, KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p<0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease). EGFR mutations were almost exclusively found in never-smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency toward association with progressive disease status. These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation, which may have a prognostic value in ADC.

[1]  Jane J. Sohn,et al.  MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. , 2010, Cancer research.

[2]  D. Haber,et al.  Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents , 2010, Nature Reviews Cancer.

[3]  Xifeng Wu,et al.  Cancer diagnosis in first-degree relatives and non-small cell lung cancer risk: results from a multi-centre case-control study in Europe. , 2009, European journal of cancer.

[4]  Y. Martinet,et al.  EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration , 2009, European Respiratory Journal.

[5]  Takayuki Kosaka,et al.  Prognostic Implication of EGFR, KRAS, and TP53 Gene Mutations in a Large Cohort of Japanese Patients with Surgically Treated Lung Adenocarcinoma , 2009, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[6]  P. Hainaut,et al.  Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. , 2007, Cancer research.

[7]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[8]  Y. Yatabe,et al.  Epidermal growth factor receptor mutations in lung cancers , 2007, Pathology international.

[9]  S. Chanock,et al.  Common Genetic Variation in TP53 Is Associated with Lung Cancer Risk and Prognosis in African Americans and Somatic Mutations in Lung Tumors , 2007, Cancer Epidemiology Biomarkers & Prevention.

[10]  N. Hanna,et al.  EGF Receptor Gene Mutations Are Common in Lung Cancers From “Never Smokers” and Are Associated With Sensitivity of Tumors to Gefitinib and Erlotinib , 2006 .

[11]  J. Minna,et al.  Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. , 2006, Journal of the National Cancer Institute.

[12]  P. Hainaut,et al.  TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. , 2005, Cancer research.

[13]  L. Liotta,et al.  Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  H. Becher,et al.  Effect of tobacco smoking on various histological types of lung cancer , 2005, Journal of Cancer Research and Clinical Oncology.

[15]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Murphy,et al.  The codon 72 polymorphic variants of p53 have markedly different apoptotic potential , 2003, Nature Genetics.

[17]  N. Tretyakova,et al.  Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers , 2002, Oncogene.

[18]  C. Harris,et al.  Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung. , 2001, Cancer research.

[19]  P. Hainaut,et al.  Patterns of p53 G-->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. , 2001, Carcinogenesis.

[20]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[21]  M. Tang,et al.  Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53 , 1996, Science.