Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer

Francesca De Nicola, Frauke Goeman, Matteo Pallocca, Francesca Sperati, Laura Pizzuti, Elisa Melucci, Beatrice Casini, Carla Azzurra Amoreo, Enzo Gallo, Maria Grazia Diodoro, Simonetta Buglioni, Marco Mazzotta, Patrizia Vici, Domenico Sergi, Luigi Di Lauro, Maddalena Barba, Edoardo Pescarmona, Gennaro Ciliberto, Ruggero De Maria, Maurizio FanciulliMarcello Maugeri-Saccà

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95%CI: 1.28–3.64, p = 0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI: 1.49–4.58, p = 0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.

Original languageEnglish
Pages (from-to)55
JournalOncogenesis
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

Fingerprint

High-Throughput Nucleotide Sequencing
Colorectal Neoplasms
Mutation
Survival
Genes
Critical Pathways
Neoplasm Genes
Proportional Hazards Models
Disease-Free Survival
Technology

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer. / De Nicola, Francesca; Goeman, Frauke; Pallocca, Matteo; Sperati, Francesca; Pizzuti, Laura; Melucci, Elisa; Casini, Beatrice; Amoreo, Carla Azzurra; Gallo, Enzo; Diodoro, Maria Grazia; Buglioni, Simonetta; Mazzotta, Marco; Vici, Patrizia; Sergi, Domenico; Di Lauro, Luigi; Barba, Maddalena; Pescarmona, Edoardo; Ciliberto, Gennaro; De Maria, Ruggero; Fanciulli, Maurizio; Maugeri-Saccà, Marcello.

In: Oncogenesis, Vol. 7, No. 7, 01.07.2018, p. 55.

Research output: Contribution to journalArticle

De Nicola, F, Goeman, F, Pallocca, M, Sperati, F, Pizzuti, L, Melucci, E, Casini, B, Amoreo, CA, Gallo, E, Diodoro, MG, Buglioni, S, Mazzotta, M, Vici, P, Sergi, D, Di Lauro, L, Barba, M, Pescarmona, E, Ciliberto, G, De Maria, R, Fanciulli, M & Maugeri-Saccà, M 2018, 'Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer', Oncogenesis, vol. 7, no. 7, pp. 55. https://doi.org/10.1038/s41389-018-0066-2
De Nicola, Francesca ; Goeman, Frauke ; Pallocca, Matteo ; Sperati, Francesca ; Pizzuti, Laura ; Melucci, Elisa ; Casini, Beatrice ; Amoreo, Carla Azzurra ; Gallo, Enzo ; Diodoro, Maria Grazia ; Buglioni, Simonetta ; Mazzotta, Marco ; Vici, Patrizia ; Sergi, Domenico ; Di Lauro, Luigi ; Barba, Maddalena ; Pescarmona, Edoardo ; Ciliberto, Gennaro ; De Maria, Ruggero ; Fanciulli, Maurizio ; Maugeri-Saccà, Marcello. / Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer. In: Oncogenesis. 2018 ; Vol. 7, No. 7. pp. 55.
@article{659ed57cf4774290853cdb5ccd6a051e,
title = "Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer",
abstract = "Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95{\%}CI: 1.28–3.64, p = 0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95{\%}CI: 1.49–4.58, p = 0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.",
author = "{De Nicola}, Francesca and Frauke Goeman and Matteo Pallocca and Francesca Sperati and Laura Pizzuti and Elisa Melucci and Beatrice Casini and Amoreo, {Carla Azzurra} and Enzo Gallo and Diodoro, {Maria Grazia} and Simonetta Buglioni and Marco Mazzotta and Patrizia Vici and Domenico Sergi and {Di Lauro}, Luigi and Maddalena Barba and Edoardo Pescarmona and Gennaro Ciliberto and {De Maria}, Ruggero and Maurizio Fanciulli and Marcello Maugeri-Sacc{\`a}",
year = "2018",
month = "7",
day = "1",
doi = "10.1038/s41389-018-0066-2",
language = "English",
volume = "7",
pages = "55",
journal = "Oncogenesis",
issn = "2157-9024",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Deep sequencing and pathway-focused analysis revealed multigene oncodriver signatures predicting survival outcomes in advanced colorectal cancer

AU - De Nicola, Francesca

AU - Goeman, Frauke

AU - Pallocca, Matteo

AU - Sperati, Francesca

AU - Pizzuti, Laura

AU - Melucci, Elisa

AU - Casini, Beatrice

AU - Amoreo, Carla Azzurra

AU - Gallo, Enzo

AU - Diodoro, Maria Grazia

AU - Buglioni, Simonetta

AU - Mazzotta, Marco

AU - Vici, Patrizia

AU - Sergi, Domenico

AU - Di Lauro, Luigi

AU - Barba, Maddalena

AU - Pescarmona, Edoardo

AU - Ciliberto, Gennaro

AU - De Maria, Ruggero

AU - Fanciulli, Maurizio

AU - Maugeri-Saccà, Marcello

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95%CI: 1.28–3.64, p = 0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI: 1.49–4.58, p = 0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.

AB - Genomic technologies are reshaping the molecular landscape of colorectal cancer (CRC), revealing that oncogenic driver mutations (APC and TP53) coexist with still underappreciated genetic events. We hypothesized that mutational analysis of CRC-linked genes may provide novel information on the connection between genetically-deregulated pathways and clinical outcomes. We performed next-generation sequencing (NGS) analysis of 16 recurrently mutated genes in CRC exploiting tissue specimens from 98 advanced CRC patients. Multiple correspondence analysis (MCA) was used to identify gene sets characterizing negative and positive outliers (patients in the lowest and highest quartile of progression-free survival, PFS). Variables potentially affecting PFS and overall survival (OS) were tested in univariate and multivariate Cox proportional hazard models. Sensitivity analyses and resampling were used to assess the robustness of genomic predictors. MCA revealed that APC and TP53 mutations were close to the negative outlier group, whereas mutations in other WNT pathway genes were in proximity of the positive outliers. Reasoning that genetic alterations interact epistatically, producing greater or weaker consequences in combination than when individually considered, we tested whether patients whose tumors carried a genetic background characterized by APC and TP53 mutations without coexisting mutations in other WNT genes (AMER1, FBXW7, TCF7L2, CTNNB1, SOX9) had adverse survival outcomes. With this approach, we identified two oncodriver signatures (ODS1 and ODS2) associated with shorter PFS (ODS1 multivariate Cox for PFS: HR 2.16, 95%CI: 1.28–3.64, p = 0.004; ODS2 multivariate Cox for PFS: HR 2.61, 95%CI: 1.49–4.58, p = 0.001). Clinically-focused and molecularly-focused sensitivity analyses, resampling, and reclassification of mutations confirmed the stability of ODS1/2. Moreover, ODS1/2 negatively impacted OS. Collectively, our results point to co-occurring driver mutations as an adverse molecular factor in advanced CRC. This relationship depends on a broader genetic context highlighting the importance of genetic interactions.

UR - http://www.scopus.com/inward/record.url?scp=85050628449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050628449&partnerID=8YFLogxK

U2 - 10.1038/s41389-018-0066-2

DO - 10.1038/s41389-018-0066-2

M3 - Article

AN - SCOPUS:85050628449

VL - 7

SP - 55

JO - Oncogenesis

JF - Oncogenesis

SN - 2157-9024

IS - 7

ER -