Secondary Somatic Mutations Restoring BRCA1/2 Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas
01 Aug 2011-Journal of Clinical Oncology (American Society of Clinical Oncology)-Vol. 29, Iss: 22, pp 3008-3015
TL;DR: Primary and recurrent BRCA1/2-mutated ovarian carcinomas are assessed to define the frequency of secondary mutations and correlate these changes with clinical outcomes and to predict resistance to platinum chemotherapy and resistance to PARP inhibitors.
Abstract: Purpose Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary mutations and correlate these changes with clinical outcomes. Methods Neoplastic cells were isolated with laser capture microdissection, and DNA was sequenced at the site of the known germline BRCA1/2 mutation. When secondary mutations were found that restored wild-type sequence, haplotyping was performed using single nucleotide polymorphisms in tumor and paired lymphocyte DNA to rule out retention of the wild-type allele. Results There were 64 primary and 46 recurrent ovarian carcinomas assessed. Thirteen (28.3%) of 46 (95% CI, 17.3% to 42.6%) recurrent carcinomas had a secondary mutation compared with two (3.1%) of 64 (95% CI, 1.0% to 10.7%) primary carcinomas (P = .0...
Citations
More filters
TL;DR: Current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness are discussed, and interesting lessons for the development of other therapies are provided.
Abstract: PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
1,643 citations
TL;DR: A better understanding of the cellular response to DNA damage will not only inform the knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.
Abstract: Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.
1,425 citations
University of Queensland1, QIMR Berghofer Medical Research Institute2, Peter MacCallum Cancer Centre3, University of Melbourne4, University of Glasgow5, South Australia Pathology6, Imperial College London7, Royal Women's Hospital8, University of Sydney9, University of New South Wales10, Victorian Life Sciences Computation Initiative11, La Trobe University12, Harvard University13, University of Chicago14, University of Western Australia15
TL;DR: It is shown that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance.
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
1,195 citations
TL;DR: Levels of mutant alleles reflected the clinical course of the disease and its treatment—for example, stabilized disease was associated with low allelic frequency, whereas patients at relapse exhibited a rise in frequency, and TAm-Seq will need to achieve a more sensitive detection limit to identify mutations in the plasma of patients with less advanced cancers.
Abstract: Plasma of cancer patients contains cell-free tumor DNA that carries information on tumor mutations and tumor burden. Individual mutations have been probed using allele-specific assays, but sequencing of entire genes to detect cancer mutations in circulating DNA has not been demonstrated. We developed a method for tagged-amplicon deep sequencing (TAm-Seq) and screened 5995 genomic bases for low-frequency mutations. Using this method, we identified cancer mutations present in circulating DNA at allele frequencies as low as 2%, with sensitivity and specificity of >97%. We identified mutations throughout the tumor suppressor gene TP53 in circulating DNA from 46 plasma samples of advanced ovarian cancer patients. We demonstrated use of TAm-Seq to noninvasively identify the origin of metastatic relapse in a patient with multiple primary tumors. In another case, we identified in plasma an EGFR mutation not found in an initial ovarian biopsy. We further used TAm-Seq to monitor tumor dynamics, and tracked 10 concomitant mutations in plasma of a metastatic breast cancer patient over 16 months. This low-cost, high-throughput method could facilitate analysis of circulating DNA as a noninvasive "liquid biopsy" for personalized cancer genomics.
1,155 citations
The Royal Marsden NHS Foundation Trust1, University of Texas MD Anderson Cancer Center2, Duke University3, Stanford University4, Cancer Research UK5, University of Pennsylvania6, Harvard University7, Peter MacCallum Cancer Centre8, University of Chicago9, Memorial Sloan Kettering Cancer Center10, Queen Mary University of London11, University College London12, Indiana University13, University Health Network14, Imperial College London15, University of Melbourne16
TL;DR: Nine major recommendations that should be taken to improve the outcome for women with ovarian cancer are outlined in this Opinion article.
Abstract: There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.
1,130 citations
References
More filters
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Abstract: Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice...
3,332 citations
"Secondary Somatic Mutations Restori..." refers background in this paper
...BRCA1/2-deficient carcinomas have decreased capacity to repair DNA and are sensitive to chemotherapy with DNA cross-linking agents such as cisplatin and carboplatin (platinum agents)(8-10) and are susceptible to synthetic lethality from poly (ADP-ribose) polymerase (PARP) inhibitors.(11-13) Women with BRCA1/2-associated ovarian carcinoma have improved survival compared with those with sporadic ovarian carcinomas when treated with platinum agents....
[...]
King's College London1, Memorial Sloan Kettering Cancer Center2, Harvard University3, University of Pennsylvania4, Cedars-Sinai Medical Center5, City of Hope National Medical Center6, University of Texas MD Anderson Cancer Center7, Lund University8, University of Cologne9, Peter MacCallum Cancer Centre10, National Institute for Health Research11, AstraZeneca12
TL;DR: Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer.
2,119 citations
"Secondary Somatic Mutations Restori..." refers background in this paper
...BRCA1/2-deficient carcinomas have decreased capacity to repair DNA and are sensitive to chemotherapy with DNA cross-linking agents such as cisplatin and carboplatin (platinum agents)(8-10) and are susceptible to synthetic lethality from poly (ADP-ribose) polymerase (PARP) inhibitors.(11-13) Women with BRCA1/2-associated ovarian carcinoma have improved survival compared with those with sporadic ovarian carcinomas when treated with platinum agents....
[...]
TL;DR: A caretaker role for BRCA1 is demonstrated in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes.
1,208 citations
"Secondary Somatic Mutations Restori..." refers background in this paper
...BRCA1/2 are tumor suppressor genes, and BRCA1/2 proteins are instrumental in repairing damaged DNA, through homologous recombination.(3,4) The vast majority of primary carcinomas in patients with BRCA1/2 mutations have deletions of the wild-type BRCA1/2 allele,(5-7) leading to a neoplasm deficient in BRCA1/2 protein....
[...]
TL;DR: Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of Cases carrying B RCA2 mutations.
Abstract: A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995–96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%–14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age 60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5′ fifth, but 8.8-fold increased risk for mutations in the 3′ fifth (95%CI 3.6–22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer–cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.
975 citations
"Secondary Somatic Mutations Restori..." refers background in this paper
...Ten percent to 15% of ovarian carcinomas occur in women with heterozygous germline mutations in BRCA1 and BRCA2 (BRCA1/2).(1,2) BRCA1/2 are tumor suppressor genes, and BRCA1/2 proteins are instrumental in repairing damaged DNA, through homologous recombination....
[...]
TL;DR: It is proposed that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and, possibly, tumorigenesis, through lack of repair or misrepair of DNA damage.
961 citations
"Secondary Somatic Mutations Restori..." refers background in this paper
...BRCA1/2 are tumor suppressor genes, and BRCA1/2 proteins are instrumental in repairing damaged DNA, through homologous recombination.(3,4) The vast majority of primary carcinomas in patients with BRCA1/2 mutations have deletions of the wild-type BRCA1/2 allele,(5-7) leading to a neoplasm deficient in BRCA1/2 protein....
[...]