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- W2589177167 abstract "206 Background: Several clinical reports have indicated increased sensitivity to DNA damaging agents and PARP inhibitors in patients with PAC arising on a background of known BRCA1/2 or PALB2 germline mutation. While the mechanism of tumorigenesis in these cancer remains unclear, it appears likely that BRCA1/2germline mutations can predispose to PAC via 2 mechanisms, only one of which requires loss of the second allele. Determination as to whether biallelic inactivation of these genes is present in the tumor may have important therapeutic implications in predicting sensitivity to PARP inhibitors and other strategies targeting DNA repair. Methods: Following approval by the IRB and human bio specimen utilization committee at MSKCC, full exon sequencing of coding regions of 28 genes including BRCA1, 2 and PALB2 using exon capture by hybridization and next generation sequencing was performed on DNA extracted from 135 PAC samples. In addition, samples were analyzed for the presence of BRCA1 promotor methylation, KRAS hotspot mutations, and genome wide loss of heterozygosity (LOH) as an exploratory assessment of number and length of LOH as a marker of homologous repair deficiency / genomic instability. All patients underwent surgery for PAC at MSKCC after year 2000. Patients were selected on the basis of survival and included if they suffered a cancer-specific death within 1 year of resection or survived at least 30 months. Results: 7 tumors had mutations in BRCA2, 1 in BRCA1 and 1 in PALB2. Of 4 BRCA2 mutated samples evaluated for LOH at the BRCA2 locus, 2 demonstrated LOH while 2 did not. There was no LOH at PALB2 in the sample where a mutation was identified. Activating KRAS mutations were identified in BRCA2 mutated tumors with and without LOH. Methylation of the BRCA1promotor regions was not identified. Conclusions: The frequency of BRCA1/2 mutation carriers was as anticipated in this population. Biallelic loss of BRCA2 or PALB2 are not required for pancreatic tumorigenesis. The benefit of PARP inhibitors in BRCA1 / 2 mutated PAC may be limited to tumors with LOH of these genes. Inactivation of BRCA1 through promoter methylation is not identified in sporadic PAC." @default.
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- W2589177167 date "2014-01-20" @default.
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- W2589177167 title "Molecular features of BRCA1/2 and PALB2 mutation associated pancreatic cancer (PAC)." @default.
- W2589177167 doi "https://doi.org/10.1200/jco.2014.32.3_suppl.206" @default.
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