title: Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway.
abstract: OBJECTIVE
  Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization.
  
  
  METHODS
  We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence.
  
  
  RESULTS
  Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression.
  
  
  CONCLUSIONS
  PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy.
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Hong
authors.initials: H
authors.lastname: Lou
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Villagran
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Im
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Sarita
authors.initials: S
authors.lastname: Polo
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Hospital Central Universitario "Dr. Antonio M Pineda," Barquisimeto, Lara State, Venezuela.
authors.forename: Ushie
authors.initials: U
authors.lastname: Odey
authors.affiliation: Unidad de Medicina Genómica, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Eligia
authors.initials: E
authors.lastname: Juárez-Torres
authors.affiliation: Unidad de Medicina Genómica, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Medina-Martínez
authors.affiliation: Servicio de Oncología, Hospital General de México, México, D.F. México.
authors.forename: Edgar
authors.initials: E
authors.lastname: Roman-Basaure
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Jason
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Roberson
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Julie
authors.initials: J
authors.lastname: Sawitzke
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Garland
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodríguez-Herrera
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Wells
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Troyer
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Francisco Castillo
authors.initials: FC
authors.lastname: Pinto
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Sara
authors.initials: S
authors.lastname: Bass
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Miriam
authors.initials: M
authors.lastname: Castillo
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland.
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Hesler
authors.initials: H
authors.lastname: Morales
authors.affiliation: Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Unidad de Medicina Genómica, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Jaime
authors.initials: J
authors.lastname: Berumen
authors.affiliation: Hospital Central Universitario "Dr. Antonio M Pineda," Barquisimeto, Lara State, Venezuela.
authors.forename: Enrique
authors.initials: E
authors.lastname: Alvirez
authors.affiliation: Instituto de Cancerologia, Guatemala City, Guatemala.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gharzouzi
authors.affiliation: Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland. deanm@mail.nih.gov.
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
mesh_terms: D000328:Adult; D000368:Aged; D052685:Alphapapillomavirus / Q000145:classification / Q000235:genetics; D014408:Biomarkers, Tumor; D002874:Chromosome Mapping; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D015870:Gene Expression; D015894:Genome, Human; D023281:Genomics; D006166:Guatemala / Q000453:epidemiology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008800:Mexico / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology* / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D014687:Venezuela / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt