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

Abstract

Purpose Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing over 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 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 phosphatidyl inositol (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 age 50. 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.

Emerging strategies for targeting PI3K in gynecologic cancer

“…ACCEPTED MANUSCRIPT 10 Investigators have suggested that alterations in the PI3K pathway may play a role in modulating the oncogenic potential of cervical cells [54,55]. Recently, Zhang and colleagues published a comprehensive review highlighting how HPV's oncogenic proteins E5, E6, E7 enhance PI3K pathway signaling via direct activation of PI3K as well as downstream AKT and rpS6K.…”

Somatic Variations in Cervical Cancers in Indian Patients

“…They identified recurrent mutations in MAPK, and mutations in genes such as HLA-B, EP300, FBXW7, NFE2L2,TP53 and ERBB2 in 79 primary squamous cell carcinomas and that of ELF3 and CBFB in 24 adenocarcinomas [6]. A study from Latin America reported mutations in PIK3CA to be a key player both in squamous and adeno cervical carcinomas [16]. Another study on cervical cancer cases of European origin identified PIK3CA, KRAS and FBXW7 to be the most mutated [17].…”

Next-Generation Sequencing-Based HPV Genotyping Assay Validated in Formalin-Fixed, Paraffin-Embedded Oropharyngeal and Cervical Cancer Specimens

“…Additional cervical cancer specimens were provided according to the ethical approval cited. 20 Two hundred sixty-six cervical cancer specimens from a separate cohort 20 were provided in accordance with the ethical approvals cited. In brief, DNA was extracted from cervical cancer tissues (5-10 mg) and stored in RNAlater using the AllPrep DNA/RNA Micro Kit (Qiagen), as directed by the manufacturer.…”

“…A large cohort of cervical cancer cases was tested by ion torrent NGS genotyping at NCI-FNLCR 20 ; the genotypes detected were not reported previously. Twenty HPV genotypes were detected in this cohort, including all 13 high-risk genotypes (16,18,31,33,35,39,45,51,52,56,58,59, and 68).…”