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Copy Number Analyses ID Gene Tied to Treatment Resistance in Ovarian Cancer

NEW YORK (GenomeWeb News) – An array-based analysis by researchers from Australia and elsewhere has identified a gene that is often missing in ovarian cancers that become resistant to liposomal doxorubicin chemotherapy, hinting that it may serve as a marker for such acquired resistance.

As they reported in today's issue of the journal Cancer Research, the researchers compared copy number profiles in pre- and post-treatment samples from almost two-dozen women with metastatic high-grade serous ovarian cancers, looking at how copy number shifts corresponded to treatment sensitivity and resistance over time. The analyses pointed to one gene that was especially prone to deletions or lower-than-usual expression in cases with acquired treatment resistance: the lipid transporter gene LRP1B.

"Currently, we have few tools to predict response to chemotherapy in the relapse setting," senior author David Bowtell, head of the Peter MacCallum Cancer Centre's Cancer Genomics and Genetic Program in Melbourne, said in a statement. "LRP1B adds to a handful of other mechanisms so far identified.

"If we can comprehensively map the mechanisms that confer resistance," he added, "we may be able to predict whether some women are likely to respond to a certain drug or not, and find ways of reversing resistance."

The high-grade serous ovarian cancer subtype, the most commonly diagnosed form of ovarian cancer, is often marked by early sensitivity to treatment that wanes over time, the study authors explained. This acquired resistance and relapse makes the disease especially difficult to defeat, leaving researchers to puzzle over the genetic and genomic shifts that accompany it.

"We were interested in identifying the molecular changes that occurred in a tumor between the time when a woman first presented for surgery and chemotherapy, and the time when the tumor recurred and eventually became resistant to chemotherapy," Bowtell explained.

Past studies have identified a handful of resistance-related mutations in ovarian cancer, he and his colleagues noted. But researchers suspected that there might be other, yet unidentified copy number alterations that could contribute to this process as well.

Indeed, the team's preliminary comparisons of copy number profiles in primary and metastatic tumors from four women with ovarian cancer indicated that copy number patterns vary between tumors from the same individual, impacting the expression of genes in the regions showing variable copy number patterns.

To explore this further — and to look at how ovarian tumor heterogeneity might influence ovarian cancer treatment response and outcomes — the team used high-resolution Affymetrix SNP 6.0 arrays to assess matched pre- and post-treatment samples from 22 women with high-grade serous tumors who had been recruited over almost a decade as part of a population-based study in Australia.

Again, the researchers frequently found sites in the genome with copy number profiles that differed between tumors from the same individual. But the extent of these differences was not uniform across the patients tested.

When they compared copy number profiles from individuals with treatment-sensitive or resistant primary tumors and tumors that did or did not respond to treatment after relapse, for example, the investigators saw that copy number changes tended to be somewhat more pronounced in cases that started out chemotherapy sensitive but went on to become resistant.

"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," Bowtell said in a statement.

Within parts of the genome that were particularly prone to copy number gain or loss in tumors that acquired treatment resistance, the team tracked down a handful of potential resistance-related genes affected by these changes.

Their top candidate: LRP1B, a lipid transporter gene falling in a chromosome 2 region that was frequently lost in resistant samples but present in matched primary tumors that had responded to treatment.

Indeed, researchers reported, lowered expression or loss of LRP1B was associated with treatment resistance in the samples from the original 22 ovarian cancer patients tested and in samples from dozens more women with high-grade serous ovarian cancer.

The team's cell line experiments suggested that bumping up the levels of LRP1B in cell lines with lower-than-usual expression of the gene can enhance response to a form of chemotherapy called liposomal doxorubicin. On the other hand, curbing LRP1B expression decreased ovarian cancer cell vulnerability to the drug.

The effect appeared to be at least somewhat specific to that treatment, the team explained, since cells missing LRP1B remained sensitive to a doxorubicin drug that lacked liposomal modifications.

"We propose that against a background of high mutation frequency, cells with LRP1B loss may be readily selected for during liposomal doxorubicin treatment," the study authors wrote, "providing an additional opportunistic advantage to the tumor."

"An investigation of a possible role of LRP1B in resistance to other chemotherapeutic agents commonly used in late-stage ovarian cancer treatment is warranted," they added.

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