Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.

Purpose: In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity.

Patients And Methods: HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations.

Cloned fusion product from a rare t(15;19)(q13.2;p13.1) inhibit S phase in vitro.

Background: Somatically acquired chromosomal translocation is a common mechanism of oncogene activation in many haematopoietic tumours and sarcomas. However, very few recurrent chromosomal translocations have been reported in more common epithelial tumours such as lung carcinomas.

Methods: We established a cell line HCC2429 from an aggressive, metastatic lung cancer arising in a young, non-smoking woman, demonstrating a t(15;19)(q13.

Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation.

Recently, the human SRBC (hSRBC) gene, a candidate tumor suppressor gene (TSG), has been mapped to the chromosomal region 11p 15.5--p15.4 where frequent allele loss has been described in lung cancer.

Current status of small peripheral adenocarcinomas of the lung and their importance to pathologists.

There has been a large amount of work done recently on small peripheral stage I adenocarcinomas that come to resection. Radiological (including proportion of ground glass opacity) and pathological features of these lesions (predominant bronchioloalveolar component, central scar with or without invasion <0.5 cm) have been shown to be prognostically favorable with cure rate approaching 100% in some series.

Genomic and gene expression profiling of minute alterations of chromosome arm 1p in small-cell lung carcinoma cells.

Genetic alterations occurring on human chromosome arm 1p are common in many types of cancer including lung, breast, neuroblastoma, pheochromocytoma, and colorectal. The identification of tumour suppressors and oncogenes on this arm has been limited by the low resolution of current technologies for fine mapping. In order to identify genetic alterations on 1p in small-cell lung carcinoma, we developed a new resource for fine mapping segmental DNA copy number alterations.

Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour.

The human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumour-suppressor gene inactivated by methylation in several cancers. In this study, we analysed the methylation and expression status of hDAB2IP in gastrointestinal tumours. The promoter region of hDAB2IP was divided into two regions (m2a and m2b) based on our previous report, and the methylation status was determined by bisulphite DNA sequencing in gastric cancer cell lines.

Aberrant methylation of SPARC in human lung cancers.

SPARC (secreted protein acidic and rich in cysteine) is an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth. We investigated loss of expression of SPARC gene and promoter methylation in lung cancers and correlated the data with clinicopathological features. We observed loss of SPARC expression in 12 of 20 (60%) lung cancer cell lines.

Somatic mutations of the HER2 kinase domain in lung adenocarcinomas.

Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non-small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations.

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

Background: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear.

Methods: We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers.

The 3p21 candidate tumor suppressor gene BAF180 is normally expressed in human lung cancer.

BAF180 encoding a subunit of the human SWI/SNF chromatin remodeling complex maps to 3p21, in a region where frequent allele loss has been detected in lung cancer. BAF180 can be mutated and has tumor suppressing properties in breast cancer. In addition, another member of this complex, hSNF5/INI1, is a known tumor suppressor gene (TSG) for malignant rhabdoid and childhood central nervous system tumors.

Aberrant methylation of Reprimo in lung cancer.

Deregulation of cell cycle inhibition contributes to human carcinogenesis. Reprimo (for stop/repress) is a newly identified mediator of the p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo expression due to promoter methylation was recently identified in pancreatic cancer.

The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers.

Purpose: Recent studies reported that clinical responsiveness to gefitinib was associated with somatic mutation of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers (NSCLC). Here, we investigated the relationship between EGFR mutation and clinicopathologic features.

Experimental Design: EGFR mutational status of 120 NSCLCs was determined mainly in EGFR exons 18 to 21 by direct sequence and correlated with clinicopathologic parameters.

Aberrant methylation of Reprimo in human malignancies.

Reprimo is a new candidate mediator of p53-mediated cell cycle arrest at the G2 phase. Loss of Reprimo gene expression accompanied by its promoter methylation was identified in pancreatic and lung cancers. Our aim was to examine the methylation status of Reprimo in a broad range of cancers.

Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.

Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC.

Two somatic biallelic lesions within and near SMAD4 in a human breast cancer cell line.

Loss of chromosome arm 18q is a common event in human pancreatic, colon, and breast cancers and is often interpreted as representing loss of one or more tumor-suppressor genes. In this article, we describe two novel biallelic deletions at chromosome band 18q21.1 in a recently characterized human breast cancer cell line, HCC-1428.

Nuclear morphometry as a biomarker for bronchial intraepithelial neoplasia: correlation with genetic damage and cancer development.

Background: Bronchial carcinomas are preceded by epithelial morphologic changes. The variation in interpretation of these grades of intraepithelial neoplasia makes it difficult to determine its natural history and utility of histopathology as a surrogate endpoint biomarker. The objective of this study was to quantitate morphologic changes of intraepitherlial neoplasia and validate its utility through correlation with histopathology, allelic loss, and cancer development.

High-resolution chromosome arm 5p array CGH analysis of small cell lung carcinoma cell lines.

Genomic amplification of regions on chromosome arm 5p has been observed frequently in small cell lung cancer (SCLC), implying the presence of multiple oncogenes on this arm. Although conventional comparative genomic hybridization (CGH) detects gross chromosomal copy number changes, gene discovery requires a higher-resolution approach in order to identify regions of alteration precisely. To identify candidate genes on this chromosome arm, we developed a high-resolution, 10-clone-per-megabase bacterial artificial chromosome CGH array for 5p and examined a panel of 15 SCLC cell lines.

Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins.

By expressing two genes (hTERT and Cdk4), we have developed a method to reproducibly generate continuously replicating human bronchial epithelial cell (HBEC) lines that provide a novel resource to study the molecular pathogenesis of lung cancer and the differentiation of bronchial epithelial cells. Twelve human bronchial epithelial biopsy specimens obtained from persons with and without lung cancer were placed into short-term culture and serially transfected with retroviral constructs containing cyclin-dependent kinase (Cdk) 4 and human telomerase reverse transcriptase (hTERT), resulting in continuously growing cultures. The order of introduction of Cdk4 and hTERT did not appear to be important; however, transfection of either gene alone did not result in immortalization.

Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection.

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM.

Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors.

The perturbations of the cytokine signaling pathway play an important role in lymphoid/hematopoietic tumors. Aberrant promoter methylation is the major mechanism of gene silencing in tumors. We examined 150 lymphoid/hematopoietic tumors or potential premalignant specimens, 55 control specimens and 12 EBV-transformed B lymphoblastoid cultures and 10 lymphoma/leukemia (L/L) or multiple myeloma (MM) cell lines for the methylation (and, in cell lines, of the expression status) of three genes involved in the cytokine signaling pathway.

Mutations of EGFR in lung cancers and their implications for targeted therapy.

Extract: The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [enzymes which phosphorylate (add phosphate groups to) tyrosine residues in proteins] is dysregulated in many human cancers and plays important roles in their development and progression. The family has four member molecules: ERBB1/EGFR/HER1 (located on chromosome 7), ERBB2/HER2 (on chromosome 17), ERBB3/ HER3 (on chromosome 12) and ERBB4/HER4 (on chromosome 2). These receptor molecules are composed of an extracellular ligand-binding domain, a transmembrane segment and an intracellular tyrosine kinase domain followed by a regulatory segment.

A randomized phase IIb trial of pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium.

Purpose: Preclinical studies suggest that inhaled budesonide may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of inhaled budesonide in smokers with bronchial dysplasia.

Experimental Design: A total of 112 smokers with more than or equal to one site of bronchial dysplasia > 1.

Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies.

HIN-1 (high in normal-1) is a putative cytokine with growth inhibitory activities and is downregulated by aberrant methylation in breast cancers. We studied HIN-1 methylation status in many types of adult and pediatric malignancies and cell lines. We examined the expression of HIN-1 mRNA in 52 cell lines and the promoter methylation status in the cell lines and in over 800 primary tumors representing 17 tumor types using methylation specific PCR.

Mutations and addiction to EGFR: the Achilles 'heal' of lung cancers?

The epidermal growth factor receptor (EGFR) gene product is a receptor tyrosine kinase (TK) that affects many important downstream pathways. The recent finding that mutations in EGFR predict the response of lung cancers to therapies that target the TK domain of the gene product has generated considerable interest. The mutations are associated with adenocarcinoma histology, oriental origin, female gender and never-smoker status.