title: Intra-tumor heterogeneity in TP53 null High Grade Serous Ovarian Carcinoma progression.
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.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain. amota@iib.uam.es.|MD Anderson International Foundation, Madrid, Spain. amota@iib.uam.es.
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.affiliation: Sistemas Genómicos, Valencia, Spain. jc.trivino@sistemasgenomicos.com.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Triviño
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Madrid, Spain. arojo@mdanderson.es.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rojo-Sebastian
authors.affiliation: Department of Molecular Cytogenetics, MD Anderson Cancer Center, Madrid, Spain. anmartinez@mdanderson.es.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Martínez-Ramírez
authors.affiliation: Department of Gynecologic Oncology, MD Anderson Cancer Center, Madrid, Spain. lchiva@mdanderson.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiva
authors.affiliation: Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain. agonzalezm@mdanderson.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Martín
authors.affiliation: MD Anderson International Foundation, Madrid, Spain. jfgarcia@mdanderson.es.|Department of Pathology, MD Anderson Cancer Center, Madrid, Spain. jfgarcia@mdanderson.es.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Garcia
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain. pgarcia@mdanderson.es.|MD Anderson International Foundation, Madrid, Spain. pgarcia@mdanderson.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia-Sanz
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain. gmoreno@iib.uam.es.|MD Anderson International Foundation, Madrid, Spain. gmoreno@iib.uam.es.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
mesh_terms: D060965:Clonal Evolution; D055028:Comparative Genomic Hybridization; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology*; D005260:Female; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D017422:Sequence Analysis, DNA; D050680:Transcription Factor DP1 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C503042:GPNMB protein, human; D008562:Membrane Glycoproteins; C493735:TFDP1 protein, human; C495901:TP53 protein, human; D050680:Transcription Factor DP1; D016159:Tumor Suppressor Protein p53