Marcadores moleculares no câncer de pulmão: papel prognóstico e sua relação com o tabagismo Molecular markers in lung cancer: prognostic role and relationship to smoking

Estudos epidemiológicos têm demonstrado um nexo causal entre tabagismo e carcinoma de pulmão. Embora a maioria dos cânceres de pulmão esteja associada com tabagismo, somente uma minoria de grandes tabagistas desenvolve essa malignidade, o que leva ao conceito de que fatores genéticos afetam a susceptibilidade individual. As principais alterações moleculares no câncer de pulmão são: genes de supressão tumoral, proto-oncogenes e fatores de crescimento, atividade da telomerase e status de metilação de promotores. Fatores estimuladores da angiogênese (fator de crescimento endotelial vascular) e fatores relacionados à proliferação e apoptose de células tumorais (receptor para fator de crescimento epidérmico, p53, K-ras, retinoblastoma, BCL-2) são bem conhecidos. Vários desses fatores genéticos foram investigados, porém nenhum deles apresentou seletividade no que diz respeito à importância prognóstica ou eficácia terapêutica. Estratégias terapêuticas para o tratamento do câncer de pulmão devem considerar essas alterações genéticas precoces para promover o seu reparo ou eliminar as células tumorais.<br>Epidemiological studies have demonstrated a causal relationship between smoking and lung cancer. Although most lung cancer cases are linked to smoking, only a minority of heavy smokers develop lung cancer, leading to the notion that genetic factors affect individual susceptibility. The principal molecular changes in lung cancer are seen in tumor suppressor genes, proto-oncogenes, growth factors, telomerase activity, and methylation status of promoters. Well-known agents include angiogenesis-stimulating factors (such as vascular endothelial growth factor), as well as factors related to tumor cell proliferation and apoptosis (epidermal growth factor receptor, p53, K-ras, retinoblastoma and BCL-2). Several of these genetic factors have already been investigated, but no single parameter has yet presented sufficient selectivity regarding prognostic value or therapeutic efficacy. Treatment strategies to cure lung cancer should focus on these early genetic lesions in order to promote their repair or to eliminate these lung cancer cells

Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas

BACKGROUND: c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas. METHODS: In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2. RESULTS: We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08–2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06–3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24–17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15–18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11–4.10 for DFS). CONCLUSIONS: c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death