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Clin Cancer Res. 2015 Dec 1;21(23):5360-70. doi: 10.1158/1078-0432.CCR-14-1837. Epub 2015 Jun 16.

Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway.

Author information

1
Basic Science Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
2
Instituto de Cancerologia, Guatemala City, Guatemala.
3
Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Gaithersburg, Maryland.
4
Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland.
5
Hospital Central Universitario "Dr. Antonio M Pineda," Barquisimeto, Lara State, Venezuela.
6
Unidad de Medicina Genómica, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
7
Servicio de Oncología, Hospital General de México, México, D.F. México.
8
Laboratory of Experimental Immunology, National Cancer Institute, Frederick, Maryland. deanm@mail.nih.gov.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

PMID:
26080840
PMCID:
PMC4668220
DOI:
10.1158/1078-0432.CCR-14-1837
[Indexed for MEDLINE]
Free PMC Article

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