Marie-Christine Aubry

DNA mismatch repair genes hMLH1, hMSH2, and hMSH6 are not inactivated in bronchioloalveolar carcinomas of the lung.

Defective DNA mismatch repair (MMR) appears to be rare in nonsmall cell carcinomas of the lung. Defective DNA MMR results from genetic or epigenetic alterations that inactivate the DNA MMR genes hMLH1 or hMSH2, and rarely hMSH6. The loss of normal DNA MMR is thought to promote tumorigenesis by accelerating the accumulation of mutations in oncogenes and tumor suppressor genes. Inactivation of hMLH1, hMSH2, and hMSH6 is observed as a loss of expression of these proteins by immunohistochemistry. Bronchioloalveolar carcinoma is a subtype of adenocarcinoma with distinctive clinical and pathologic features.

Non-neoplastic pulmonary lymphoid proliferations

Non-neoplastic pulmonary lymphoid proliferations encompass a spectrum of disease from small airway bronchiolar disease to diffuse interstitial disease. They include follicular bronchiolitis (FB), nodular lymphoid hyperplasia (NLH), and lymphocytic interstitial pneumonia (LIP). FB is characterized by the presence of hyperplastic lymphoid follicles with germinal centers, exquisitely bronchiolocentric. Patients with FB not uncommonly suffer from connective tissue disease such as rheumatoid arthritis or immunodeficiency. The differential diagnosis of FB includes other small airway diseases such as chronic bronchiolitis or constrictive bronchiolitis. In contrast, LIP is an interstitial lung disease with diffuse marked septal thickening by small lymphocytes, with admixed plasma cells and histiocytes. Patients with LIP often present with autoimmune disorders such as Sjogrens syndrome. Chronic hypersensitivity pneumonia and non-specific interstitial pneumonia enter the differential diagnosis of LIP. Patients with NLH are typically asymptomatic and present with solitary or multiple nodular infiltrates. The lung parenchyma is focally obliterated by a mass comprised of fibrosis admixed with a dense polymorphous lymphoid infiltrate, often with numerous germinal centers. By immunohistochemistry, the lymphoid infiltrate is predominantly CD3 + T-cells with CD20 + B-cells forming the germinal centers. The plasma cells and lymphocytes are polyclonal. NLH needs to be distinguished from low-grade lymphoma, mainly MALT lymphoma.

Genetic variations in multiple drug action pathways and survival in advanced-stage non-small cell lung cancer treated with chemotherapy.

7009 Background: The prognosis for patients with advanced-stage non-small cell lung cancer (NSCLC) remains very poor. Inherited predictive markers may assist treatment optimization. Genetic variants in glutathione metabolism (GSH), DNA repair, cell cycle and epidermal growth factor receptor (EGFR) pathways were systematically investigated for their association with survival in advanced-stage NSCLC treated with commonly used chemotherapy drugs. METHODS A total of 894 tagging single nucleotide polymorphisms (SNPs) in 70 genes from the four pathways were genotyped in a 1076-patient cohort. Association with overall survival was analyzed at single-SNP and whole-gene levels within all patients and major drug combination subgroups. RESULTS Poorer survival was observed in patients with genetic variations in MAP3K1 from the EGFR pathway (HR=1.25, 95% CI=1.05-1.50) and GSS from the GSH pathway (HR=1.45, 95% CI=1.20-1.77). From stratified analysis of the subgroup treated with platinum-taxane doublet, a predictive yet opposite effect on survival was observed in MAP3K1 (HR=1.38, 95% CI=1.11-1.72) versus in RAF1 (HR=0.64, 95% CI=0.5-0.82) variations of the EGFR pathway. In the subgroup treated with platinum-gemcitabine doublet, RAF1 and GPX5 (GSH pathway) variations showed protective effects on survival (HR=0.54, 95% CI=0.38-0.77; HR=0.67, 95% CI=0.52-0.85, respectively), whereas NRAS (EGFR pathway) and GPX7 (GSH pathway) variations showed hazardous effects on survival (HR=1.91, 95% CI=1.30-2.8; HR=1.83, 95% CI=1.27-2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis. CONCLUSIONS Genetic variations in genes involved in the EGFR and glutathione pathways may be associated with overall survival among patients with advanced-stage NSCLC treated with platinum-, taxane, and/or gemicitabine combinations.

Abstract LB-186: Genetic variants and risk of lung cancer in never-smokers: A genome-wide association study

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-186.