3 research outputs found
Intra-tumor heterogeneity in TP53 null high grade serous ovarian carcinoma progression
[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.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.Peer Reviewe
Intra-tumor heterogeneity in TP53 null High Grade Serous Ovarian Carcinoma progression
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 strategiesThis 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