A Five-Gene Signature and Clinical Outcome in Non–Small-Cell Lung Cancer

Chen, Hsuan Yu; Yu, Sung-Liang; Chen, Chun-Houh; Chang, Gee Chen; Chen, Chih Yi; Yuan, Ang; Cheng, Chu-Yun; Wang, Chien Hsun; Terng, Harn Jing; Kao, Shu Fang; Chan, Wing Kai; Li, Han Ni; Liu, Chun Chi; Singh, Sher; Chen, Wei-Jen; Chen, Jeremy J.W.; Yang, Pan Chyr

doi:10.1056/nejmoa060096

Cited by 856 publications

(696 citation statements)

References 32 publications

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“…375 Microarray analysis of NSCLC yielded a five-gene signature that predicted relapse-free and overall survival, and ERBB3 was one of these five genes. 378 There is therefore mounting evidence that ERBB3 expression supports lung malignancy.…”

Section: Respiratory Tissuesmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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Section: Respiratory Tissuesmentioning

confidence: 99%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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“…49 Recent studies have shown that gene-expression profiles can distinguish lung cancer patients at particularly high risk of disease recurrence. 50,51 These genomic signatures have not, however, been evaluated for their ability to predict patterns of failure.…”

Section: Biological Predictorsmentioning

confidence: 99%

Factors associated with the development of brain metastases

Hubbs

Boyd

Hollis

et al. 2010

Cancer

120

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BACKGROUND The risk of developing brain metastases after definitive treatment of locally advanced nonsmall cell lung cancer (NSCLC) is approximately 30%-50%. The risk for patients with early stage disease is less defined. The authors sought to investigate this further and to study potential risk factors. METHODS The records of all patients who underwent surgery for T1-T2 N0-N1 NSCLC at Duke University between the years 1995 and 2005 were reviewed. The cumulative incidence of brain metastases and distant metastases was estimated by using the Kaplan-Meier method. A multivariate analysis assessed factors associated with the development of brain metastases. RESULTS Of 975 consecutive patients, 85% were stage I, and 15% were stage II. Adjuvant chemotherapy was given to 7%. The 5-year actuarial risk of developing brain metastases and distant metastases was 10%(95% confidence interval [CI], 8-13) and 34%(95% CI, 30-39), respectively. Of patients developing brain metastases, the brain was the sole site of failure in 43%. On multivariate analysis, younger age (hazard ratio [HR], 1.03 per year), larger tumor size (HR, 1.26 per cm), lymphovascular space invasion (HR, 1.87), and hilar lymph node involvement (HR, 1.18) were associated with an increased risk of developing brain metastases. CONCLUSIONS In this large series of patients treated surgically for early stage NSCLC, the 5-year actuarial risk of developing brain metastases was 10%. A better understanding of predictive factors and biological susceptibility is needed to identify the subset of patients with early stage NSCLC who are at particularly high risk. Cancer 2010;116:5038-46.

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“…Desmocollin-3 in large-cell lung carcinoma V Monica et al with the final histopathological diagnosis, desmocollin-3 reactivity was present in all four squamous carcinomas and 1 of the 7 large-cell cancers, whereas TTF-1 was expressed in 7 of the 20 adenocarcinomas and 2 of the 7 large-cell cancers. The 17 double marker negative tumors were either adenocarcinomas 13 or LCCs. 4 Immunohistochemical tests run in parallel on the corresponding histological samples (18 surgical specimens and 13 bronchial biopsies of inoperable patients) had a partially overlapping reactivity.…”

Section: Cytological Materialsmentioning

confidence: 99%

“…12 Major advances in the phenotypic profiling of different lung cancer subtypes were obtained by molecular analysis of a large number of genes, which seemed to provide different signatures in different histological types, according to their up-or downregulation. [13][14][15] In a recent study on non-smallcell lung carcinoma, 16 four genes were found upregulated in squamous carcinomas by at least 20-fold compared to adenocarcinomas and/or normal lung parenchyma (PKP1, DSC3, p63 and CK17). Among these, the highest difference between squamous carcinoma and adenocarcinoma (and also between cancer and normal tissue) was observed for DSC3, which codes for desmocollin-3, a constitutive protein of desmosomes.…”

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confidence: 97%

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

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A Five-Gene Signature and Clinical Outcome in Non–Small-Cell Lung Cancer

Abstract: Our five-gene signature is closely associated with relapse-free and overall survival among patients with NSCLC.

Cited by 856 publications

References 32 publications

The ERBB3 receptor in cancer and cancer gene therapy

The ERBB3 receptor in cancer and cancer gene therapy

Factors associated with the development of brain metastases

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

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