Genetic mechanisms of resistance to chemotherapy in the most common and the most lethal form of ovarian cancer may provide clues as to why that cancer initially succumbs to the drugs and then resists them, according to a large study published in Nature and reported by Catharine Paddock, Ph.D., in Medical News Today on May 29 (http://www.medicalnewstoday.com/articles/294575.php).
According to Russell Vang, M.D., Ie-Ming Shih, M.D., Ph.D., and Robert J. Kurman, M.D., writing in Advanced Anatomical Pathology and published on the National Center for Biotechnology Information website, high-grade serous carcinomas are characterized by certain mutations and genetic instability, may originate from intraepithelial carcinoma in the fallopian tube and develop rapidly. They initially respond to chemotherapy better than low-grade serous carcinomas (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745605/).
The study of the genetic mechanisms of chemoresistance in high-grade serous ovarian carcinoma (HSC), the most malignant form of ovarian cancer, was enabled by the Australian Ovarian Cancer Study (AOCS), which collects ovarian cancer tissue samples from donors. Funding came from the National Health and Medical Research Council (Australia), Worldwide Cancer Research, Cancer Australia, Ovarian Cancer Action (UK) and Ovarian Cancer Australia.
Resistance to chemotherapy is a major factor in HSC, which accounts for 70 percent of all ovarian cancers, 60 percent of deaths related to the disease and 80,000 deaths annually worldwide. According to the recent study's co-senior author and professor David Bowtell of the Peter MacCallum Cancer Centre in Melbourne, Australia, "For decades clinicians around the world have watched HSCs shrink under attack from chemotherapy, before returning aggressively months or years later."
To find out how and why the aggressive cancer changes from initially being vulnerable, to eventually becoming highly resistant to chemotherapy, Bowtell and his colleagues sequenced the genomes of 114 HSC samples from 92 patients. They collected samples at various stages in disease progression - some at diagnosis, some following successful and unsuccessful treatment, and others immediately after death, creating the first genetic map of how HSC evolves in response to chemotherapy.
Prof. Bowtell described four genetic changes in the cancer cells: "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."