p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading

Emanuela Guerra, Alessia Cimadamore, Pasquale Simeone, Giovanna Vacca, Rossano Lattanzio, Gerardo Botti, Valentina Gatta, Marco D'Aurora, Barbara Simionati, Mauro Piantelli, Saverio Alberti

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. Methods: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. Results: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. Conclusions: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.

Original languageEnglish
Article number649
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - Aug 18 2016

Fingerprint

Cathepsin D
Joints
Breast Neoplasms
Neoplasms
Recurrence
INDEL Mutation
Neoplasm Grading
Metalloproteases
Missense Mutation
Cadherins
Estrogen Receptors
Sequence Analysis
Case-Control Studies
Exons
Lymph Nodes
Hormones
Phenotype

Keywords

  • Bcl-2
  • Breast cancer
  • Cathepsin D
  • Metastatic relapse
  • Prognostic indicators
  • RAS
  • TP53

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

Cite this

Guerra, E., Cimadamore, A., Simeone, P., Vacca, G., Lattanzio, R., Botti, G., ... Alberti, S. (2016). p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading. BMC Cancer, 16(1), [649]. https://doi.org/10.1186/s12885-016-2713-3

p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading. / Guerra, Emanuela; Cimadamore, Alessia; Simeone, Pasquale; Vacca, Giovanna; Lattanzio, Rossano; Botti, Gerardo; Gatta, Valentina; D'Aurora, Marco; Simionati, Barbara; Piantelli, Mauro; Alberti, Saverio.

In: BMC Cancer, Vol. 16, No. 1, 649, 18.08.2016.

Research output: Contribution to journalArticle

Guerra, E, Cimadamore, A, Simeone, P, Vacca, G, Lattanzio, R, Botti, G, Gatta, V, D'Aurora, M, Simionati, B, Piantelli, M & Alberti, S 2016, 'p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading', BMC Cancer, vol. 16, no. 1, 649. https://doi.org/10.1186/s12885-016-2713-3
Guerra, Emanuela ; Cimadamore, Alessia ; Simeone, Pasquale ; Vacca, Giovanna ; Lattanzio, Rossano ; Botti, Gerardo ; Gatta, Valentina ; D'Aurora, Marco ; Simionati, Barbara ; Piantelli, Mauro ; Alberti, Saverio. / p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
@article{4cf6001ed60a44d291bd6b5462332c2d,
title = "p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading",
abstract = "Background: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. Methods: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 {\%}) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. Results: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. Conclusions: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.",
keywords = "Bcl-2, Breast cancer, Cathepsin D, Metastatic relapse, Prognostic indicators, RAS, TP53",
author = "Emanuela Guerra and Alessia Cimadamore and Pasquale Simeone and Giovanna Vacca and Rossano Lattanzio and Gerardo Botti and Valentina Gatta and Marco D'Aurora and Barbara Simionati and Mauro Piantelli and Saverio Alberti",
year = "2016",
month = "8",
day = "18",
doi = "10.1186/s12885-016-2713-3",
language = "English",
volume = "16",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - p53, cathepsin D, Bcl-2 are joint prognostic indicators of breast cancer metastatic spreading

AU - Guerra, Emanuela

AU - Cimadamore, Alessia

AU - Simeone, Pasquale

AU - Vacca, Giovanna

AU - Lattanzio, Rossano

AU - Botti, Gerardo

AU - Gatta, Valentina

AU - D'Aurora, Marco

AU - Simionati, Barbara

AU - Piantelli, Mauro

AU - Alberti, Saverio

PY - 2016/8/18

Y1 - 2016/8/18

N2 - Background: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. Methods: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. Results: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. Conclusions: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.

AB - Background: Traditional prognostic indicators of breast cancer, i.e. lymph node diffusion, tumor size, grading and estrogen receptor expression, are inadequate predictors of metastatic relapse. Thus, additional prognostic parameters appear urgently needed. Individual oncogenic determinants have largely failed in this endeavour. Only a few individual tumor growth drivers, e.g. mutated p53, Her-2, E-cadherin, Trops, did reach some prognostic/predictive power in clinical settings. As multiple factors are required to drive solid tumor progression, clusters of such determinants were expected to become stronger indicators of tumor aggressiveness and malignant progression than individual parameters. To identify such prognostic clusters, we went on to coordinately analyse molecular and histopathological determinants of tumor progression of post-menopausal breast cancers in the framework of a multi-institutional case series/case-control study. Methods: A multi-institutional series of 217 breast cancer cases was analyzed. Twenty six cases (12 %) showed disease relapse during follow-up. Relapsed cases were matched with a set of control patients by tumor diameter, pathological stage, tumor histotype, age, hormone receptors and grading. Histopathological and molecular determinants of tumor development and aggressiveness were then analyzed in relapsed versus non-relapsed cases. Stepwise analyses and model structure fitness assessments were carried out to identify clusters of molecular alterations with differential impact on metastatic relapse. Results: p53, Bcl-2 and cathepsin D were shown to be coordinately associated with unique levels of relative risk for disease relapse. As many Ras downstream targets, among them matrix metalloproteases, are synergistically upregulated by mutated p53, whole-exon sequence analyses were performed for TP53, Ki-RAS and Ha-RAS, and findings were correlated with clinical phenotypes. Notably, TP53 insertion/deletion mutations were only detected in relapsed cases. Correspondingly, Ha-RAS missense oncogenic mutations were only found in a subgroup of relapsing tumors. Conclusions: We have identified clusters of specific molecular alterations that greatly improve prognostic assessment with respect to singularly-analysed indicators. The combined analysis of these multiple tumor-relapse risk factors promises to become a powerful approach to identify patients subgroups with unfavourable disease outcome.

KW - Bcl-2

KW - Breast cancer

KW - Cathepsin D

KW - Metastatic relapse

KW - Prognostic indicators

KW - RAS

KW - TP53

UR - http://www.scopus.com/inward/record.url?scp=84982221121&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982221121&partnerID=8YFLogxK

U2 - 10.1186/s12885-016-2713-3

DO - 10.1186/s12885-016-2713-3

M3 - Article

AN - SCOPUS:84982221121

VL - 16

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

IS - 1

M1 - 649

ER -