How deadly ovarian cancer evades chemotherapy

The largest complete DNA analysis of ovarian cancer in the world has revealed new insight into the genetic twists and turns a deadly form of the disease takes to outsmart chemotherapy. Published in the journal Nature, this groundbreaking work features contributions from several Australian facilities.

The researchers utilised whole-genome sequencing of 114 tumour and germline DNA samples of high-grade serous ovarian carcinoma (HSC) from 92 patients - collected either at diagnosis, following successful and unsuccessful treatment, or immediately after death - to investigate how cancer evolves to evade initially effective chemotherapy. HSC accounts for 70% of all ovarian cancers and 60% of ovarian cancer-related deaths.

Team leader David Professor Bowtell, from the Peter MacCallum Cancer Centre, said the study revealed four key mechanisms by which initially vulnerable ovarian cancers go through genetic changes and become resistant to common chemotherapy. He stated, “In two of the mechanisms, cancer cells find a way of restoring their ability to repair damaged DNA and thereby resist the effects of chemotherapy; in another, cancer cells ‘hijack’ a genetic switch that enables them to pump chemotherapy drugs out of harm’s way.

“A further mechanism sees the molecular structure of the cancer tissue shift and reshape, such that sheets of ‘scar tissue’ appear to block chemotherapy from reaching its target.”

According to co-senior author Professor Sean Grimmond, formerly of The University of Queensland’s Institute for Molecular Bioscience (IMB), the latter technique is “fundamentally different to other cancers, where the disease is driven by smaller but more gradual changes to individual genes”.

“It is essentially shattering big chunks of the cell’s hard drive and moving them around, rather than just changing bits in the files,” he said.

Dr Ann-Marie Patch (formerly of IMB), who interpreted the results, said the use of cutting-edge technology was crucial to the discovery. She explained, “By using the latest sequencing techniques, we have been able to find scars from breaks in the DNA that have helped us better define the genes involved in allowing tumours to grow.”

Professor Bowtell said there had until now been little information to guide clinicians when selecting treatment for women whose ovarian cancer has returned, with clinicians watching HSCs shrink under attack from chemotherapy only to return aggressively months or years later.

“By completely sequencing the cancers, sampled at different stages of disease, for the first time we can map their evolution under the selective pressure of chemotherapy and begin work on better interventions,” he said.

Co-senior author Professor Anna DeFazio, from the Westmead Millennium Institute, added, “Each of our findings suggest a refined approach to drug selection in recurrent ovarian cancer, which could include bypassing drugs that are unlikely to be effective.

“This particular view of such a complex disease has never been seen before, and we believe it will lead to more women receiving treatment better suited to their particular cancer, all over the world.”

Image caption: Co-first authors Dr Dale Garsed (left), Dr Elizabeth Christie (centre) and Dr Dariush Etemadmoghadam (right) in the Molecular Genomics facility at the Peter MacCallum Cancer Centre.