EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100273949EGA dataset EGAD00001002739EGAGermline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.Taylor Renea A RA, Fraser Michael M, Livingstone Julie J, Espiritu Shadrielle Melijah G SM, Thorne Heather H, Huang Vincent V, Lo Winnie W, Shiah Yu-Jia YJ, Yamaguchi Takafumi N TN, Sliwinski Ania A, Horsburgh Sheri S, Meng Alice A, Heisler Lawrence E LE, Yu Nancy N, Yousif Fouad F, Papargiris Melissa M, Lawrence Mitchell G MG, Timms Lee L, Murphy Declan G DG, Frydenberg Mark M, Hopkins Julia F JF, Bolton Damien D, Clouston David D, McPherson John D JD, van der Kwast Theodorus T, Boutros Paul C PC, Risbridger Gail P GP, Bristow Robert G RGhereditary breast ovarian cancer, FAD1, BRCC2, GLM3, BRCA1, BRCA2, DmelCG30169, 30169, dmbrca2, PNCA2, CG30169, CG13583, brca2, CG13584, Fancd1, AI256696, BcDNA:SD25109, FAD, FACD., FANCB, FANCD, Familiar breast and Ovarian cancer syndrome, AW045498, FANCD1, BROVCA2, XRCC11, RAB163hereditary prostate cancer, hereditary breast ovarian cancer, cancer of the prostate, Prostate Neoplasms, GLM3, BRCA1, BRCA2, Neoplasms, familial, DmelCG30169, CG30169, CG13583, CG13584, BcDNA:SD25109, Prostatic Cancer, Neoplasm, Prostatic Cancers, Familiar breast and Ovarian cancer syndrome, NOS, Mutations., FANCD1, BROVCA2, XRCC11, Cancer of Prostate, Prostate Cancers, FAD1, BRCC2, 30169, dmbrca2, Cancers, cancer of prostate, PNCA2, Prostate Neoplasm, brca2, Fancd1, AI256696, Prostatic Neoplasm, Cancer of the Prostate, FAD, FANCB, FANCD, AW045498, Prostatic, prostate cancer, PC, Prostate Cancer, RAB163, FACD, Prostate, Cancerhereditary breast ovarian cancer, distinct., FAD1, Drives, BRCC2, GLM3, Prostate Neoplasms, BRCA1, BRCA2, Neoplasms, DmelCG30169, 30169, dmbrca2, Cancers, PNCA2, CG30169, CG13583, brca2, Prostate Neoplasm, CG13584, Fancd1, AI256696, Mutations, Prostatic Neoplasm, BcDNA:SD25109, Cancer of the Prostate, FAD, FANCB, FANCD, Prostatic Cancer, Familiar breast and Ovarian cancer syndrome, AW045498, Neoplasm, Prostatic Cancers, Prostatic, FANCD1, BROVCA2, XRCC11, Cancer of Prostate, Prostate Cancer, RAB163, FACD, Prostate, Cancer, Prostate CancersKto, Materials, insensitive, neoplasia, DmelCG30169, LFP, Genome Stability, Tumor, Mutations, SSN5, Relative, BcDNA:SD25109, diseases, Microdissections, Familiar breast and Ovarian cancer syndrome, Tnrc11, diseases and disorders, Atypical Ductal, BROVCA2, Benson syndrome, Trap230, Gonadectomies, CDCD1, treatment, increased, amyloidosis, TNRC11, human disease, Pca-1, FAD1, A130035F20, BRCC2, Genomes, NUT6, cell process disease, tumor disease, YCR080W, C2, neoplasm (disease), twy, OPA-1, PNCA2, allergic reaction, Prostatic Neoplasm, aggressive behaviour, Cancer of the Prostate, Therapies, Homo sapiens disease, siren1, tumor, MED12S, RAB163, FACD, Tumors, Ductal Hyperplasias, Therapy, hereditary breast ovarian cancer, TRALP, Carcinoma, cancer of the prostate, Noninfiltrating Intraductal Carcinoma, Hyperplasia, IDC, CAGH45, BRCA1, BRCA2, Pdnp1, Srb8/KTO/TRAP230, MED12, familial, arteria cerebri communicans posterior, familial cutaneous lichen, neoplastic disease, Aggressions, tumours, CG13583, CG13584, FGS1, Med12, 4833416E15Rik, Intraductal, metastatic disease, C76301, breast ductal carcinoma in situ, Hyperplasias, Relative Risks, Ductal Hyperplasia, Pca, PCA, Diseases, POSTERIOR, Genetic Materials, NOS, XRCC11, AXPC1, Genetic Material, CDDC, Carcinomas, PCS, FPL, Intraductal Carcinoma, LMN1, Risk, resistant, OHDOX, CMT2B1, l(3)76BDc, Anaphylaxis, common, LMNC, cancer of prostate, Treatments, brca2, Genomic, Fancd1, AI256696, disease, metastatic, FAD, Patient, Material, metastatic tumor, AW045498, PC-1, SRB8, TRAP230, Cistron, other neoplasm, Genomic Stabilities, Ly-41, accessory, Prostate, other disease, Passive, CD203c, NPP1, localised, AU044581, GLM3, Prostate Neoplasms, Kto/Med12, GIG1, Neoplasms, invasive carcinoma, Gene, stalk, Mopa, HOPA, Genomic Stability, supernumerary, CG30169, CMD1A, NEOPL, TRALPUSH, Stability, Atypical Ductal Hyperplasia, dTrap230, sensitive, Instabilities, Core Genome, Genomic Instabilities, CG8491, Prostatic Cancers, disease or disorder, ARC240, Ductal Carcinoma In Situ, FANCD1, EMD2, Cancer of Prostate, increase in risk, Atypical, neoplasm, sensitivity, Genome Instabilities, Prostate Cancers, Npps, Passive Cutaneous, FLVCR, LMNL1, localized, Genetic, A630079M02, biparietal Alzheimer disease, FPLD2, Accessory Genome, NOPAR, Noninfiltrating Intraductal, tumour, med12/kto, lichen amyloidosis, culm, non-neoplastic, PRO1, HGPS, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), TNRC11L, FANCB, aggression, Clients, FANCD, Prostatic, disorder, MFSD7B, LDP1, DmelCG8491, Neoplastic Growth, Cancer, hereditary prostate cancer, axis, disorders, OPA1, medical condition, Cistrons, Pangenome, Client, Atypical Ductal Hyperplasias, Cutaneous Anaphylaxis, metastatic neoplasm, Stabilities, M6S1, neoplastic growth, disease management., AI428932, Prostatic Cancer, Neoplasm, condition, Genome Stabilities, Relative Risk, Gonadectomy, LGMD1B, RGD1304617, Castrations, Noninfiltrating Intraductal Carcinomas, increased number, Risks, 30169, dmbrca2, choanal atresia, Noninfiltrating, Cancers, disease of cellular proliferation, Prostate Neoplasm, 230kDa, present in greater numbers in organism, FPLD, Pan-genome, Genome Instability, Therapeutic, PCARP, physical aggression, metastatic tumour, prostate cancer, PC, Treatment, E-NPP1, ttw, OKS, DCIS, Instability, dTRAP230, Prostate Cancer, Genome, NEOPLASMS BENIGN, Neoplasia, Intraductal CarcinomasfalseCPCG BRCA2 - samplesAligned sequence data from 14 Prostate cancer samples with BRCA2 mutations2018-03-06 17:49:38EGAD00001002739960628067867EGAC00001000010EGAS00001001615