Nineteen of the 20 nations with the highest cervical cancer death rates are in sub-Saharan Africa. Now an international team has published the first comprehensive genomic study of cervical cancers in sub-Saharan Africa, with a focus on tumors from 212 Ugandan patients with cervical cancer. Their findings were published by Gagliardi et al in Nature Genetics.
“Large-scale genomics studies like this are important, particularly in underrepresented ancestry groups, to understand molecular phenotypes of these cancers, which can lead to improved treatment options,” wrote the authors.
“This study is novel as the first cervical cancer study in which the majority of patients were positive for HIV,” said study coauthor Akinyemi I. Ojesina, MD, PhD, of the University of Alabama at Birmingham. “This allowed identification of genomic features that distinguish HIV-positive and HIV-negative patients.”
“It is also novel for the identification of unique genomic features associated with the African cohort compared with The Cancer Genome Atlas,” added Dr. Ojesina. The Cancer Genome Atlas includes genomic analysis of many cancers, including 307 cervical cancer tumors from places other than sub-Saharan Africa.
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Study Background, Methods, and Findings
Persistent infection by human papillomavirus (HPV) is necessary, but not sufficient, to cause cervical cancer. The cancer can be prevented with an HPV vaccine, and it can be detected early by Papanicolaou smear, but these resources are scarce in lower- and middle-income areas that have a high rate of HIV infection.
Researchers started by looking at mutational changes in the DNA of the tumor cells. Restricting that hunt just to locations in the genome that code for expressed portions of genes is a simpler way to search, but the current study “is the first cervical cancer study to focus on whole-genome sequencing of all samples—as opposed to whole-exome—leading to identification of noncoding alterations,” said Dr. Ojesina.
Another level of analysis was looking at expression of gene transcripts to see which genes were overexpressed and which were downregulated. This helps identify pathways used by the tumor to drive cancer growth, and that, in turn, can suggest possible treatments.
Part of the expression analysis also involved looking at epigenetic changes that can affect gene regulation. These included looking for the addition or removal of methyl groups on DNA bases, or changes in the methylation or acetylation of the histone proteins that help compact the human chromosome. Histone variants that can regulate gene expression were found in various tumors of the Ugandan population.
Another part of the genomic analysis was finding which types of HPV were present in tumors. Two HPV types commonly associated with cervical cancer are HPV-16 and HPV-18. Each virus type has variants, all descended from a common ancestor, and those variants that are from a single HPV type are called a clade. The variants for HPV-16 are contained in clade A9, and the variants for HPV-18 are contained in clade A7. The current study was able to describe molecular characteristics associated with each clade, including clusters of differential gene expression and clade-associated dysregulation. The A7-infected tumors, for example, showed gene expression patterns that pointed to pathways linked to extracellular matrix, cell adhesion, and migration, which are signs of a more aggressive tumor.
The current study also found differences among the tumors depending on whether the HPV was inserted into human chromosomes or not. For HPVs that were inserted into the chromosomes, the locations of the insertions differentially affected gene expression.
Finally, the researchers found that certain insertions in the tumors of Ugandan patients led to expression of endogenous retroviral sequences, and upregulation of these sequences was associated with histone modifications. These endogenous retrovirus sequences—found in normal chromosomes—are remnants of ancient retroviral infections that make up about 8% the human genome. Normally they are silenced in human cells, but they can be activated in human disease.
Disclosure: For full disclosures of the study authors, visit nature.com.
