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Sequencing Study Scrutinizes Resistance, Recurrence Mutations in Ovarian Cancer

NEW YORK (GenomeWeb) – A genomic study of ovarian cancer published online today in Nature highlighted some of the genetic and genomic features found in high-grade serous ovarian carcinoma tumors with sensitivity, resistance, or acquired resistance to conventional platinum-based treatment for the disease. 

Researchers from Australia, the UK, and elsewhere did whole-genome sequencing on tumor and matched normal samples from 92 individuals with high-grade serous ovarian cancer whose primary tumors had a range of treatment responses. They also looked at the sequences of samples from end-stage cases that had acquired treatment resistance. 

Together, these sequences provided a look at mutations that were particularly common in primary tumors with resistant or refractory treatment responses, as well as alterations associated with treatment resistance acquired over time. 

"Collectively, our findings underscore the heterogeneity and apparent adaptability of the [high-grade serous carcinoma] genome under the selective pressure of chemotherapy, and indicate that overcoming resistance to conventional chemotherapy will require a diversity of approaches," corresponding author David Bowtell, a pathology researcher affiliated with Australia's Peter MacCallum Cancer Centre, the University of Melbourne, and Imperial College London, and his co-authors wrote. 

Genomic studies done on ovarian cancer so far have demonstrated the widespread structural variation that tends to mark these tumors, the team noted. But despite advances made in understanding genetic features of the disease, not much has changed on the ovarian cancer treatment front. 

For the most part, high-grade serous ovarian tumors are treated with platinum-based chemotherapy, which often prompts a temporary clinical response that all too often gives way to relapsed forms of the disease demonstrating acquired treatment resistance. 

In an effort to understand this process, Bowtell and colleagues did whole-genome sequencing on tumor-normal sample sets from 92 high-grade serous ovarian cancer patients, generating 52-fold average coverage of each tumor and 40-fold coverage of germline genomes, on average. 

To that, they added transcriptome sequencing and array-based microRNA expression, copy number, and methylation profiling of the 114 tumors obtained from these individuals. 

As in the past, the team found recurrent TP53 and BRCA1 mutations in the primary ovarian tumors, along with methylation changes expected to inactivate the BRCA1 gene. 

Nearly one-fifth of the original tumors contained copy number gains or amplifications involving CCNE1 — alterations that were more common in tumors without BRCA1 or BRCA2 pathway problems. 

Extra copies of the CCNE1 gene were particularly common in primary tumors with resistance or refractory treatment responses, the researchers reported, while the presence of BRCA1 or BRCA2 mutations often heralded treatment success. 

Primary tumors that successfully dodged chemotherapy also tended to contain gene breaks affecting several tumor suppressor genes, including RB1, PTEN, RAD51B, and NF1. 

While the group did not detect recurrent, actionable point mutations in the relapsed samples, it did pick up on germline mutations in the BRCA1 and BRCA2 that reverted back to wild-type sequences for the genes in sub-clones within a handful of tumors that acquired resistance. 

Other features found in tumors with acquired resistance included identified declines in methylation of BRCA1's promoter or shifts in the ovarian cancer subtypes present in primary tumors compared to those with acquired resistance in the same individual. 

Meanwhile, the team's search for resistance- or recurrence-related promoter rearrangements uncovered recurrent fusions affecting the promoter of a gene called ABCB1, which codes for the multi-drug resistant protein 1 (MDR1). In at least some tumors with acquired resistance, this fusion appeared to enhance the activity of a drug efflux pump that tosses drugs such as the chemotherapeutic agent paclitaxel out of cells. 

"Identification of patients with this novel fusion event may allow clinicians to prioritize treatment with chemotherapy that is not a substrate of MDR1, more targeted use of MDR1 inhibitors, and use of new PARP inhibitors that are poor MDR1 substrates," the study's authors noted. 

Nevertheless, they cautioned that the adaptability and heterogeneity of ovarian tumors underscore the multi-faceted approaches likely required to prevent ovarian cancer from dodging treatment.