An aggressive subtype of stage I lung adenocarcinoma with molecular and prognostic characteristics typical of advanced lung cancers

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Abstract

Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N= 351) identified as highrisk by the 10-gene signature displayed a 4-fold increased risk of death [HR= 3.98; 95% confidence interval (CI), 1.73-9.14], with a 3-yearoverall survivalof 84.2%(95%CI, 78.7-89.7) comparedwith 95.6%(92.4-98.8) inlow-risk patients. The analysisof TCGAcohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment.

Original languageEnglish
Pages (from-to)62-72
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

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Lung Neoplasms
Genes
Confidence Intervals
Atlases
Adenocarcinoma of lung
Early Detection of Cancer
Paraffin
Proteomics
Methylation
Formaldehyde
Neoplasms
Research Design
Biomarkers
Genome
Gene Expression
Mutation
Mortality
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "An aggressive subtype of stage I lung adenocarcinoma with molecular and prognostic characteristics typical of advanced lung cancers",
abstract = "Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N= 351) identified as highrisk by the 10-gene signature displayed a 4-fold increased risk of death [HR= 3.98; 95{\%} confidence interval (CI), 1.73-9.14], with a 3-yearoverall survivalof 84.2{\%}(95{\%}CI, 78.7-89.7) comparedwith 95.6{\%}(92.4-98.8) inlow-risk patients. The analysisof TCGAcohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment.",
author = "Elisa Dama and Valentina Melocchi and Fabio Dezi and Stefania Pirroni and Carletti, {Rose Mary} and Daniela Brambilla and Giovanni Bertalot and Monica Casiraghi and Patrick Maisonneuve and Massimo Barberis and Giuseppe Viale and Manuela Vecchi and Lorenzo Spaggiari and Fabrizio Bianchi and {Di Fiore}, {Pier Paolo}",
year = "2017",
month = "1",
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doi = "10.1158/1078-0432.CCR-15-3005",
language = "English",
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T1 - An aggressive subtype of stage I lung adenocarcinoma with molecular and prognostic characteristics typical of advanced lung cancers

AU - Dama, Elisa

AU - Melocchi, Valentina

AU - Dezi, Fabio

AU - Pirroni, Stefania

AU - Carletti, Rose Mary

AU - Brambilla, Daniela

AU - Bertalot, Giovanni

AU - Casiraghi, Monica

AU - Maisonneuve, Patrick

AU - Barberis, Massimo

AU - Viale, Giuseppe

AU - Vecchi, Manuela

AU - Spaggiari, Lorenzo

AU - Bianchi, Fabrizio

AU - Di Fiore, Pier Paolo

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N= 351) identified as highrisk by the 10-gene signature displayed a 4-fold increased risk of death [HR= 3.98; 95% confidence interval (CI), 1.73-9.14], with a 3-yearoverall survivalof 84.2%(95%CI, 78.7-89.7) comparedwith 95.6%(92.4-98.8) inlow-risk patients. The analysisof TCGAcohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment.

AB - Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, that is, at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N= 351) identified as highrisk by the 10-gene signature displayed a 4-fold increased risk of death [HR= 3.98; 95% confidence interval (CI), 1.73-9.14], with a 3-yearoverall survivalof 84.2%(95%CI, 78.7-89.7) comparedwith 95.6%(92.4-98.8) inlow-risk patients. The analysisof TCGAcohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment.

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U2 - 10.1158/1078-0432.CCR-15-3005

DO - 10.1158/1078-0432.CCR-15-3005

M3 - Article

AN - SCOPUS:85009938332

VL - 23

SP - 62

EP - 72

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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