Expert Sees Major Genomic Knowledge Gaps in Cervical Cancer

Published: Tuesday, Jan 19, 2016
Murty Vundavalli, PhD

Murty Vundavalli, PhD

More than 20 years ago, Murty Vundavalli, PhD, was among the first researchers to characterize genetic abnormalities in cervical cancer.1 Today, in his laboratory at Columbia University, Vundavalli continues working to understand the genetic and epigenetic aspects of cervical cancer in an attempt to elucidate prognostic markers of response to treatment. Through genomewide studies, Vundavalli and colleagues have identified a variety of genomic alterations specific to cervical cancer, including amplification of the HER2 gene in squamous cell carcinoma of the cervix.1 Currently, they are evaluating a predictive biomarker of apoptotic response to combination drug therapy.2

OncLive: What are the central genetic events underlying the development of cervical cancer?

Vundavalli: The development of invasive cervical cancer proceeds by a distinct series of morphological changes in squamous epithelium called cervical intraepithelial neoplasia (CIN). CINs have varying potential to progress to invasive cancer. Genetic changes that occur in CIN can be considered as primary or central events that cause cervical cancer. Identifying a list of such genetic hits in CINs and invasive cervical cancer provides tools for early detection, predicting risk of progression of CINs, and in testing as targets for treatment.

Recent high-throughput whole-genome single nucleotide polymorphism (SNP) arrays and sequencing methods have provided some clues about the recurrent genomic aberrations in cervical cancer. Copy number alterations of chromosomal regions involving gains of 3q, 5p, and 20q have been shown to be some of the earliest genomic changes. These are currently being used as biomarkers of early detection and risk prediction of CINs.

The mutation spectrum of genes identified by recent next-generation sequencing approaches seems to represent relatively late events. These recurrent somatic mutations would serve as central targets against specific gene(s)/pathway(s) for developing therapies.

How has our understanding of the genomics of cervical cancer evolved in the past decade?

The genomic alterations that contribute to the development of cervical cancer are relatively less understood compared with other epithelial cancers such as breast and ovarian carcinomas. This shortage of knowledge about causal genetic mutations in cervical cancer has been overcome in the last decade by extraordinary progress due to innovations in array and next-generation sequencing technologies. We now have a broad understanding of focal copy number alterations (such as gains of chromosomal regions 1q, 3q, 5p, 20q, and losses on 3p, 2q, 11q), gene expression signatures, gene fusions, HPV integration sites, mutation spectrum in genes and, to a lesser extent, of epigenetic modifications.

Further understanding of relationships between this mutational spectrum and the role it plays in specific genetic pathways will facilitate identification of targets for therapies.

How has this knowledge affected development of novel targeted therapies?

Among the genomic changes identified so far, the newly identified oncogenic driver mutations in genes such as PIK3CA, MAPK1, EP300, FBXW7, ERRB2, HLA-B, PTEN, TP53, STK11, KRAS, NFE2L2, ELF3, and CBFB, may eventually benefit from targeted therapies. However, it is currently unclear as to which of these will serve as biomarkers of therapy response to cervical cancer pending functional and clinical investigations. For example, mutations in PI3K/AKT pathway and ERBB2 may be targetable by specific tyrosine kinase inhibitor agents as in other tumor types. So far, no such clearly identified targeted therapies exist for cervical cancer.

What are the most significant unanswered questions relating to the genomics of cervical cancer?

Although the recent unfolding of the molecular characterization of cervical cancer forms a backbone in our understanding of the genetics of cervical cancer, we are still limited in a number of areas of research. The incidence of cervical cancer differs geographically, likely accounting for etiological factors such as tobacco and oral contraceptive use, differences in incidence of high-risk HPV types, promiscuity, and parity.

However, differences in the genomic landscape of cervical cancer among various populations with specific etiologic exposures are still not known. Whether there are differences in genomic alterations in high- versus low-prevalence countries remains to be clarified.

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