Sir Peter MacCallum Department of Oncology - Research Publications
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ItemTandem duplication of chromosomal segments is common in ovarian and breast cancer genomes(WILEY, 2012-08)The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome.
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ItemMultiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer(NATURE PUBLISHING GROUP, 2019-03-20)ABCB1 encodes Multidrug Resistance protein (MDR1), an ATP-binding cassette member involved in the cellular efflux of chemotherapeutic drugs. Here we report that ovarian and breast samples from chemotherapy treated patients are positive for multiple transcriptional fusions involving ABCB1, placing it under the control of a strong promoter while leaving its open reading frame intact. We identified 15 different transcriptional fusion partners involving ABCB1, as well as patients with multiple distinct fusion events. The partner gene selected depended on its structure, promoter strength, and chromosomal proximity to ABCB1. Fusion positivity was strongly associated with the number of lines of MDR1-substrate chemotherapy given. MDR1 inhibition in a fusion positive ovarian cancer cell line increased sensitivity to paclitaxel more than 50-fold. Convergent evolution of ABCB1 fusion is therefore frequent in chemotherapy resistant recurrent ovarian cancer. As most currently approved PARP inhibitors (PARPi) are MDR1 substrates, prior chemotherapy may precondition resistance to PARPi.
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ItemNo evidence for PALB2 methylation in high-grade serous ovarian cancer(BIOMED CENTRAL LTD, 2013-04-12)BACKGROUND: High-grade serous ovarian cancers are a distinct histological subtype of ovarian cancer often characterised by a dysfunctional BRCA/Fanconi anaemia (BRCA/FA) pathway, which is critical to the homologous recombination DNA repair machinery. An impaired BRCA/FA pathway sensitises tumours to the treatment with DNA cross-linking agents and to PARP inhibitors. The vast majority of inactivating mutations in the BRCA/FA pathway are in the BRCA1 and BRCA2 genes and occur predominantly in high-grade serous cancer. Another member of the BRCA/FA pathway, PALB2 (FANCN), was reported to have been inactivated by DNA methylation in some sporadic ovarian cancers. We therefore sought to investigate the role of PALB2 methylation in high-grade serous ovarian cancers. FINDING: PALB2 methylation was investigated in 92 high-grade serous ovarian cancer samples using methylation-sensitive high-resolution melting analysis. DNA methylation of PALB2 was not detected in any of the ovarian cancer samples investigated. CONCLUSION: Epigenetic silencing by DNA methylation of PALB2 is not a common event in high-grade serous ovarian cancers.
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ItemNo Preview AvailableThe responses of research participants and their next of kin to receiving feedback of genetic test results following participation in the Australian Ovarian Cancer Study(NATURE PUBLISHING GROUP, 2013-06)PURPOSE: The generation of clinically significant genetic data during research studies raises a number of ethical issues about the feedback of this information to research participants. Little is known about research participants' experiences of this practice. METHODS: This qualitative interview study investigated research participants' (n = 10) or their nominated next of kin's (relatives) (n = 15) experiences of receiving BRCA1 and BRCA2 genetic test information following participation in the Australian Ovarian Cancer Study. RESULTS: Interviewees had mixed responses to receiving feedback. The participants of the Australian Ovarian Cancer Study were more positive about receiving feedback, acknowledging that the genetic information may be useful for their kin. Relatives frequently described themselves as initially distressed at receiving feedback, particularly those who were unaware of the participation of their mothers in the Australian Ovarian Cancer Study. The participants of the Australian Ovarian Cancer Study and their relatives expressed an intention to disseminate the information to relatives following confirmation of the result. CONCLUSION: We suggest that research participants be encouraged to discuss their participation with family members from the outset. We also outline a number of different strategies for providing feedback to research participants and their next of kin that may lessen the immediate negative impact of receiving feedback of research results.
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ItemNo Preview AvailableBRCA Mutation Frequency and Patterns of Treatment Response in BRCA Mutation-Positive Women With Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group(AMER SOC CLINICAL ONCOLOGY, 2012-07-20)PURPOSE: The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. PATIENTS AND METHODS: Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. RESULTS: Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-gradeserous, 17.1%); [corrected] 44% had no reported family history of breast orovarian cancer.Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. CONCLUSION: BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history.