Intra-tumor heterogeneity in TP53 null High Grade Serous Ovarian Carcinoma progression
Entity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
BioMed CentralDate
2015-11-30Citation
10.1186/s12885-015-1952-z
BMC Cancer 15.1 (2015): 940
ISSN
1471-2407DOI
10.1186/s12885-015-1952-zFunded by
This work has been supported by grants from the AECC network-2012, Telemarató 2013, Instituto de Salud Carlos III (ISCIII) (PI13/00132 and RETIC-RD12/0036/0007), GEIS award 2013, and by the Community of Madrid (S2010/BMD-2303). AM is a predoctoral student supported by FPU fellowship (Spanish Education Ministry). PGS is founded by postdoc contracts from the AECC Scientific Foundation.Project
Comunidad de Madrid. S2010/BMD-2303/RECAREEditor's Version
http://dx.doi.org/10.1186/s12885-015-1952-zSubjects
High grade serous carcinoma; Ovary cancer; TP53 null; Intra-tumor heterogeneity; MedicinaRights
© 2015 Mota et al.Abstract
Background: High grade serous ovarian cancer is characterised by high initial response to chemotherapy but
poor outcome in the long term due to acquired resistance. One of the main genetic features of this disease
is TP53 mutation. The majority of TP53 mutated tumors harbor missense mutations in this gene, correlated
with p53 accumulation. TP53 null tumors constitute a specific subgroup characterised by nonsense, frameshift
or splice-site mutations associated to complete absence of p53 expression. Different studies show that this
kind of tumors may have a worse prognosis than other TP53 mutated HGSC.
Methods: In this study, we sought to characterise the intra-tumor heterogeneity of a TP53 null HGSC
consisting of six primary tumor samples, two intra-pelvic and four extra-pelvic recurrences using exome
sequencing and comparative genome hybridisation.
Results: Significant heterogeneity was found among the different tumor samples, both at the mutational and
copy number levels. Exome sequencing identified 102 variants, of which only 42 were common to all three
samples; whereas 7 of the 18 copy number changes found by CGH analysis were presented in all samples.
Sanger validation of 20 variants found by exome sequencing in additional regions of the primary tumor and
the recurrence allowed us to establish a sequence of the tumor clonal evolution, identifying those populations that
most likely gave rise to recurrences and genes potentially involved in this process, like GPNMB and TFDP1.
Using functional annotation and network analysis, we identified those biological functions most significantly
altered in this tumor. Remarkably, unexpected functions such as microtubule-based movement and lipid
metabolism emerged as important for tumor development and progression, suggesting its potential interest
as therapeutic targets.
Conclusions: Altogether, our results shed light on the clonal evolution of the distinct tumor regions identifying the
most aggressive subpopulations and at least some of the genes that may be implicated in its progression
and recurrence, and highlights the importance of considering intra-tumor heterogeneity when carrying out
genetic and genomic studies, especially when these are aimed to diagnostic procedures or to uncover
possible therapeutic strategies
Files in this item
Google Scholar:Mota, Alba
-
Triviño, Juan Carlos
-
Rojo-Sebastian, Alejandro
-
Martínez-Ramírez, Ángel
-
Chiva, Luis
-
González-Martín, Antonio
-
García, Juan F.
-
Garcia-Sanz, Pablo
-
Moreno Bueno, Gema
This item appears in the following Collection(s)
Related items
Showing items related by title, author, creator and subject.
-
Corrigendum to “Prostaglandin F2a-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity” [Neoplasia 21 (2019) 1073–1084]
Jiménez-Segovia, Alba; Mota, Alba; Rojo-Sebastián, Alejandro; Barrocal, Beatriz; Rynne-Vidal, Ángela; García-Bermejo, María Laura; Gómez-Bris, Raquel; Hawinkels, Lukas J A C; Sandoval, Pilar; García-Escudero, Ramón; López-Cabrera, Manuel; Moreno Bueno, Gema; Fresno Escudero, Manuel; Stamatakis Andriani, Konstantinos
2020-05 -
Prostaglandin F 2α-induced prostate transmembrane protein, androgen induced 1 mediates ovarian cancer progression increasing epithelial plasticity
Jiménez-Segovia, Alba; Mota, Alba; Rojo-Sebastián, Alejandro; Barrocal, Beatriz; Rynne-Vidal, Ángela; García-Bermejo, Mara-Laura; Gómez-Bris, Raquel; Hawinkels, Lukas J.A.C.; Sandoval, Pilar; García-Escudero, Ramón; López-Cabrera, Manuel; Moreno Bueno, Gema; Fresno Escudero, Manuel; Stamatakis Andriani, Konstantinos; Centro de Biología Molecular Severo Ochoa (CBMSO); Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-IP)
2019 -
Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas
Moreno Bueno, Gema; Salvador, Fernando; Martín, Alberto Lancina; Floristán, Alfredo; Cuevas, Eva P.; Santos, Vanesa L.; Montes, Amalia; Morales, Saleta; Castilla, María Ángeles; Rojo-Sebastián, Alejandro; Martínez, Alejandra Nacarino; Hardisson Hernáez, David Alonso; Csiszár, Katalin; Portillo Pérez, Francisco; Peinado, Héctor; Palacios, José Luis; Cano, Amparo
2011-09-01