Genome Sequencing Hints at New Targets for Cervical Cancer

Jane de Lartigue, PhD
Published: Thursday, Jan 14, 2016
Cervical cancer is a prime example of how early detection of disease can significantly impact patient mortality. Over the past several decades, the rates of cervical cancer have declined dramatically in developed countries with access to effective screening programs. But for patients who slip through the cracks and present with advanced stages of disease, the picture is considerably bleaker and cervical cancer continues to represent a significant burden worldwide.

Notorious for its high metastatic activity and ability to rapidly develop resistance to chemotherapy and radiation therapy, cervical cancer has also proved unresponsive to many of the molecularly targeted therapies that have emerged in recent decades, the exception being the antiangiogenic agent bevacizumab, which the FDA approved in 2014 in combination with paclitaxel and either cisplatin or topotecan for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.

The lack of success has in large part resulted from a poor understanding of the molecular background of cervical cancer. With technological advancements in genome sequencing, researchers are now gaining a more detailed picture of the genetic drivers of cervical cancer and the important role that the human papillomavirus (HPV), responsible for the vast majority of cervical cancer cases, plays in molding the genetic profile of this disease.

Slow Therapeutic Progress

At one time, cervical cancer was the most common cause of cancer-related mortality for women in the United States, but major advancements in screening and prevention during the past half-century have significantly improved this picture. The development of the Pap test, allowing physicians to detect precancerous changes in the cervix, has been heralded as one of the most successful cancer screening programs ever. Meanwhile, the Nobel Prize-winning identification of a causative link between the common viral infection HPV and cervical cancer served as a driving force behind the development of HPV vaccines in an effort to prevent infection before it can lead to cancer.

But that’s where the good news ends for cervical cancer. In parts of the United States where access to screenings and uptake of vaccinations are poor, cervical cancer rates remain high, and in developing countries it is still the second- leading cause of cancer-related mortality.

Although the overall survival rate for cervical cancer in the United States is 68%, this rate declines dramatically as the disease progresses. Patients who have already developed advanced cervical cancer represent a substantial unmet medical need, and improvements in treatment options have been slow to materialize.

Sequencing Provides New Targets

Mutational Load Studied

The vast majority of clinical trials of targeted therapies in cervical cancer have been performed in unselected patient populations. Researchers have learned from past experience that this can often mask the effects of these drugs, which may only be effective against certain molecular backgrounds.

In an effort to develop more effective therapies, the focus has shifted to improving our understanding of the genetic underpinnings of cervical cancer. The International Cancer Genome Consortium (ICGC) is undertaking efforts to collect genomic, transcriptomic, and epigenomic data from 50 different tumor types, including squamous cell carcinoma (SCC) of the cervix, by coordinating large-scale cancer genome studies.

Significant Mutations in Cervical Cancer

Significant Mutations in Cervical Cancer

Researchers developed this portrait of significant mutations in cervical cancer using whole-exome, -genome, and –transcriptome sequencing of tumor samples. Mutations in TP53 and ERBB2 in squamous cell carcinomas and in PIK3CA and KRAS in adenocarcinomas were identified from separate analyses focusing on genes previously reported as mutated in the Catalog of Somatic Mutations in Cancer (COSMIC) database.

Ojesina AI, Lichtenstein L, Freeman SS, et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014;506(7488):371-375.

The cervical cancer study is being carried out in the United States by The Cancer Genome Atlas (TCGA). Among 308 cervical cancer donors, researchers have identified 194 simple somatic mutations thus far. The rate of somatic mutations, a phenomenon known as mutational load, varies substantially between different tumor types, ranging from 0.1 mutations/ megabase (Mb) in tumors like acute myeloid leukemia to >60 mutations/Mb in lung cancer and melanoma. By comparison, the median mutational load in cervical tumors is 4.3 mutations/ Mb.

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