Abstract C121: Genomic characterization of invasive cervical cancer in Guatemala and Venezuela: Common activation of the PIK3CA pathway.

Abstract

Cervical cancer represents the most dramatic cancer health disparity of women in the world, with over 270,000 deaths annually, concentrated in poor, rural, and indigenous populations. Guatemala and Venezuela are illustrative of this disparity as cervical cancer is the predominant cause of cancer cases and deaths in women. The average age of the subjects is 50, and smoking and oral contraceptive use is low. The affected women have an average of 6 children and adeno- or adenosquamous pathologies represent 25% of the tumors. To determine the genomic changes in invasive tumors, we initiated a prospective collection of invasive cervical cancer tissue. To determine the most frequently mutated genes we sequenced the exomes of 23 tumors in the Ion Torrent Proton and followed up with targeted sequencing of genes by Ampliseq in an additional 280 tumors. The exome sequence revealed potential driver mutations in several known cancer genes such as PTEN, PIK3CA, TSC1, SETD2, HRAS, PTCH, ARID1A, ARID4A and RB1. Targeted resequencing in a larger set of tumors of commonly mutated genes in the COSMIC database (PIK3CA, TP53, STK11, PTEN, KRAS, HRAS, and CDKN2A) revealed 40% mutation in PIK3CA and 11% in PTEN (a negative regulator of the PI kinase pathway). TP53 and STK11 were significantly mutated (10 and 8% of tumors, respectively) but HRAS, KRAS and CDKN2A at a very low level (0-2%). The PIK3CA mutations were concentrated in the known activating sites in the helical domain (E542K and E545K). To determine HPV stain types we amplified the HPV L1 gene found detectable in HPV in 96% of samples with HPV16 in 53%, HPV18 in 12%, HPV45 in 10% and HPV 26, 31, 33, 35, 39, 52, 56, 58, 67, 68, 69, and 73 in 0.8-4.9% of samples. In conclusion, invasive cervical cancers display frequent mutation of the helical domain of PIK3CA and activation of the PI kinase pathway, suggesting that targeted inhibition of this pathway may provide an avenue for therapy in this largely untreatable, common cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C121. Citation Format: Michael Dean, Eduardo Gharzouzi, Enrique Alvirez, Guillermo Villagran, Ushie Odey, Julie Sawitzke, Joe Boland, Hong Lou, Meredith Yeager. Genomic characterization of invasive cervical cancer in Guatemala and Venezuela: Common activation of the PIK3CA pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C121.