Somatic Variations in Cervical Cancers in Indian Patients

Abstract

There are very few reports that describe the mutational landscape of cervical cancer, one of the leading cancers in Indian women. The aim of the present study was to investigate the somatic mutations that occur in cervical cancer. Whole exome sequencing of 10 treatment naïve tumour biopsies with matched blood samples, from a cohort of Indian patients with locally advanced disease, was performed. The data revealed missense mutations across 1282 genes, out of 1831 genes harbouring somatic mutations. These missense mutations (nonsynonymous + stop-gained) when compared with pre-existing mutations in the COSMIC database showed that 272 mutations in 250 genes were already reported although from cancers other than cervical cancer. More than 1000 novel somatic variations were obtained in matched tumour samples. Pathways / genes that are frequently mutated in various other cancers were found to be mutated in cervical cancers. A significant enrichment of somatic mutations in the MAPK pathway was observed, some of which could be potentially targetable. This is the first report of whole exome sequencing of well annotated cervical cancer samples from Indian women and helps identify trends in mutation profiles that are found in an Indian cohort of cervical cancer.

Leveraging Methylation Alterations to Discover Potential Causal Genes Associated With the Survival Risk of Cervical Cancer in TCGA Through a Two-Stage Inference Approach

“…It is previously found that the members of the ZNF family interact with nucleic acids, proteins, and small molecules and are involved in a variety of crucial molecular processes in cervical tumor cells at replication, transcriptional, and translational levels. Thus, ZNF605 and ZNF266 may be potentially targetable ( Das et al, 2016 ; The Cancer Genome Atlas Research Network, 2017 ; Li et al, 2018 ). OSTC can regulate gamma-secretase ( Wilson et al, 2011 ) while this secretase affects the ability of HPV pseudo-viruses infection in both human HaCat cells and mouse cells ( Huang et al, 2010 ).…”

The landscape of somatic mutations in Indonesian cervical cancer is predominated by the PI3K pathway

“…With the emergence of tumor targeting drugs such as tyrosine kinase inhibitors, targeting the tumor based on its genomic profile rather than its histological background, it is important to study the prevalence of targetable oncogenic driver mutations throughout diverse ethnical cancer populations from diverse geographic areas. The prevalence of somatic mutations in cervical cancer was investigated previously in other cervical cancer cohorts worldwide from the US (N=80) [21], Norway/Mexico (N=100/15) [12], China (N=285) [23], the Netherlands (N=301) [20], France (N=29) [25], Hong Kong (N=15) [22], Guatemala/Venezuela/Mexico (N=280/40/325) [24], to India (N=10) [26], using varying techniques, from whole genome and/or exome sequencing [12,13,26], direct sequencing [23], to oncopanel analysis [20,21,25] or a combination of techniques [22,24]. This is the first study to describe the prevalence of driver mutations in an Indonesian cervical cancer cohort.…”

“…However, lower frequencies were also described in Norway (15%) and China (12%) [12,23]. And in a recent study from India, whole exome sequencing was performed on 10 FIGO stage 3b SCCs, with no PIK3CA mutations detected at all [26]. PIK3CA mutations lead to an altered production of the catalytic subunit p110α of the enzyme phosphatidylinositol 3-kinase (PI3K), allowing the PI3K pathway to signal without regulation, leading to uncontrolled cell growth, proliferation and survival.…”

“…Over the past few years, several research groups, including ours, have evaluated the genomic alterations of very small to quite large cohorts of cervical cancer patients [12,[20][21][22][23][24][25][26]. And very recently, The Cancer Genome Atlas (TCGA) Research Network published their integrated genomic and molecular characterization of cervical cancer [13].…”

Leveraging Methylation Alterations to Discover Potential Causal Genes Associated with the Survival Risk of Cervical Cancer in TCGA through a Two-stage Inference Approach

“…It is previously found that the members of the ZNF family interact with nucleic acids, proteins and small molecules and are involved in a variety of crucial molecular processes in cervical tumor cells at replication, transcriptional and translational levels. Thus, ZNF605 and ZNF266 may be potentially targetable[87][88][89]. OSTC can regulate gamma-secretase[90] while this secretase affects the ability of HPV pseudo-viruses infection both in human HaCat cells and mouse cells[91].In summary, compared with the tests via individual prediction methods, it is demonstrated that HMP greatly improves statistical power by combining dependent…”