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Gene loss in ovarian cancer subtype linked to chemotherapy resistance
The deletion of the gene LRP1B is associated with the development of chemotherapy resistance in women with the high-grade serous cancer subtype of ovarian cancer whose disease recurs after treatment, according to study results.
High-grade serous cancer (HGSC) accounts for approximately 65% of ovarian cancer deaths. Women with advanced HGSC are initially responsive to chemotherapy, but most relapse and the disease becomes less responsive to treatment, according to background information in the study.
Researchers sought to identify the molecular changes in a tumor between the time a woman is first presented for surgery and chemotherapy and the time when the tumor recurs and becomes resistant to treatment, according to David Bowtell, PhD, head of the Cancer Genomics and Genetic Program at the Peter MacCallum Cancer Centre in Melbourne, Australia.
The study is one of the first to investigate patient tumor samples as the mechanism responsible for chemotherapy resistance in HGSC ovarian cancer, according to Bowell and colleagues.
Researchers analyzed metastatic lesions, then paired pre-treatment and post-treatment tumor samples from 22 patients for spatial and temporal genomic variation.
“Spatial variation is a measure of genomic heterogeneity in different deposits of tumor present at primary surgery — variation that the tumor could draw on to evolve over time, especially in the face of chemotherapy,” Bowtell said in a press release. “Temporal variation gives us an indication of how much the tumor changes over time and after one or more lines of chemotherapy.”
Researchers compared the level of genomic change among women who were initially chemotherapy sensitive with those who were resistant to chemotherapy. Tumors that were initially sensitive to chemotherapy but turned resistant evolved further than those that were resistant from the outset, study results showed.
“We were surprised by the extent of variation that was present among the tumor deposits collected at surgery and by how far the tumors could evolve during therapy,” Bowtell said. “The existence of multiple cancer genomes in an individual patient could provide many opportunities for the cancer to circumvent chemotherapy and may help explain why it has been so difficult to make progress with this disease.”
The most frequent genomic change was a deletion and/or downregulation of a member of a family of proteins that transforms lipids into cells known as LRP1B.
Researchers validated their findings by examining the effect a gain or loss of LRP1B would have on ovarian cancer cell lines.
LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin for women during treatment, according to researchers.
“We propose that against a background of high mutation frequency, cells with LRP1B loss in the clinical setting may be readily selected during liposomal doxorubicin treatment, providing an additional opportunistic advantage to the tumor,” Bowtell and colleagues wrote.
Bowtell and colleagues identified the deletion or downregulation of LRP1B as a significant tool to predict response to chemotherapy.
“An investigation of a possible role of LRP1B in resistance to other chemotherapeutic agents commonly used in late-stage ovarian cancer treatment is warranted,” the researchers concluded.