EGAGenomicsIllumina HiSeq 2000;https://ega-archive.org/datasets/EGAD0000100086528EGA dataset EGAD00001000865EGABladder CancerBladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.Cazier J-B JB, Rao S R SR, McLean C M CM, McLean C M CM, Walker A K AK, Wright B J BJ, Jaeger E E M EE, Kartsonaki C C, Marsden L L, Yau C C, Camps C C, Kaisaki P P, Taylor J J, Catto J W JW, Tomlinson I P M IP, Kiltie A E AE, Hamdy F C FCWalia Mannu K MK, Ho Patricia Mw PM, Taylor Scott S, Ng Alvin Jm AJ, Gupte Ankita A, Chalk Alistair M AM, Zannettino Andrew Cw AC, Martin T John TJ, Walkley Carl R CRcancer of bladder, urinary bladder carcinoma, patient., WGS, tumor of the bladder, carcinoma of the bladder, cancer of the bladder, bladder carcinoma, carcinoma bladder, Bladder Cancer, cancer of the urinary bladder, carcinoma of bladder, carcinoma of urinary bladder, bladder cancer, cancer of urinary bladder, BLC, carcinoma of the urinary bladder, urinary bladder cancerbeta[[3]]-Tub, Osteosarcoma of bone (disorder), Osteochondrosarcoma, CRAMP, DmelCG17117, biological signaling, dp53, Osteogenic Sarcomas, p50, FALL39, 5'-cyclic monophosphate, antigen NY-CO-13, p53, 143391_i_at, beta3 TU, Tumor, betaTub3, LFS1, Tp53, l(3)05745, 5'-Cyclic AMP, AV083133, Osteogenic Sarcoma, PTHrP[38-94], DMP53, Cyclic adenylic acid, PTHR, bbl, osteogenic sarcoma, CAP-18, Dmp53, anon-EST:Liang-2.13, Osteoblastic osteosarcoma, tumor suppressor p53, C13orf8, TP53, Sarcomas, 1323/07, PTHrP[107-139], clone 2.13, BCC7, HHM, cAMP, Creb, D.m.BETA-60D, Sarcoma of Bone, BDE2, beta-Tub6D, dmp53, ZNF828, CREB, 3', T, DmP53, 1422/04, Osteoblastic sarcoma, Osseous Sarcoma, B3t, DmelCG3401, Sarcoma, Trp53, Dp53, no ICD-O subtype (morphologic abnormality), PTHrP, signaling process, betaTub60C, phosphoprotein p53, Parathyroid hormone-like protein, PTH-like, beta3-tubulin, beta[[3]]-tubulin, TRP53, CG17117, osteosarcoma (disease), p50/tubulin, single organism signaling, Tumors, beta-Tub60D, PTH-rP, CG10873, Osteosarcoma of bone, Dmbeta3, Dm-HTH, 3526402H21Rik, Osteogenic sarcoma, Osteosarcoma - disorder, PTHRP, 2310001E10Rik, malignant, BETA 60D, prac, beta3t, beta3-Tub, CAP18, Osteostatin, Osteogenic, 5'-phosphate, CAMP, Pthrp, Xp53, 3t, Cyclic AMP, 5'-cyclic phosphate, [M]Osteosarcoma NOS, p53/tubulin, NOS, bfy, beta[[3]] tubulin, sarcoma of osteoid, activation, PTHrP[1-36], Tub60D, HTH, Hth, Osteosarcomas, CG33336, Skeletal sarcoma, Bone Sarcoma, beta-tub, Sarcoma of the Bone, LL37, FALL-39, CHAMP, DmelCG33336, D-p53, beta60C, osteoid sarcoma, CG3401, initiation, Maintenances., beta3Tub, beta3TUB, PLP, 5'-(hydrogen phosphate), Dm-P53, l(3)86Ca, Osteosarcoma, beta3, Creb-1, 5'-CYCLIC-MONOPHOSPHATE, dtl, bone tissue neoplasm, signalling, Tub, DTB3, Meis1, hth1, OS, hth2, no ICD-O subtype, signalling process, betatub60D, Adenosine 3', ADENOSINE-3', P53, p44, bhy, Osteosarcoma Tumors, Osteosarcoma Tumor, adenosine 3', CG31325, betaTub, osteosarcomamalignant Growth, Cyclin-dependent kinase inhibitor 1A (P21, dp53, WEX9, cancer of the urinary bladder, pp21, neoplasia, 21 kDa polypeptide, OPHN3, bladder cancer, protein, p21[dacapo], Tumor, betaTub3, Tp53, Mutations, dysfunctional, Relative, protein polypeptide chains, DMP53, Associations, bbl, Causes of Death, Dmp53, protein aggregate, Fs(3)Hor, tumor suppressor p53, ophn3, TP53, Progression, strong, 1323/07, DmelCG2684, me75, Genomes, BCC7, cell process disease, tumor disease, neoplasm (disease), beta-Tub6D, P21 protein, dmp53, E(Sev-CycE)2B, T, DmP53, 1422/04, proteins, behavioral response to stimulus, Melanoma differentiation-associated protein 6, number of, NTef2, p21WAF, D4S234, D17Mit170, T1, CA, B3t, DmelCG3401, carcinoma of the bladder, malignant neoplasm, Dp53, p16Xic2, Exacerbation, phosphoprotein p53, Urinary, stage, carcinoma of urinary bladder, P15, tumor, cdkn1a, CG17117, D4S234E, p50/tubulin, single-organism behavior, Tumors, CDKN1A, CG10873, malignancy, cip1, P21, Disease Exacerbation, MRX30, neoplastic disease, extra or missing physical or functional parts, Tl3, Tl2, tumours, partial functionality, Fs(3)Sz11, 3t, tumor of the bladder, p21, vesica urinaria, organ system cancer, p23, precocious, Detrusor Muscles, p27, bfy, Tub60D, HTH, Hth, CAP20, hPAK3, cancer of bladder, beta-tub, Risk, Death Cause, Relative Risks., DmelCG33336, Cdkn1, CG3401, carcinoma of bladder, beta3Tub, beta3TUB, bpak, CIP1, lacks function of type, Waf1, Detrusor Muscle, WAF1, low functionality, early, DTB3, CDKN2B, hth1, Cip1, hth2, Melanoma differentiation-associated protein, p27[Dap], pak3-A, Horka, MDA-6, P53, CG2684, p44, Fs(3)Horka, Death Causes, bhy, bPAK, bladder, FAT, other neoplasm, cancer, BC011290, CG31325, CDKN1, betaTub, urinary bladder cancer, urinary bladder carcinoma, beta[[3]]-Tub, Detrusor Urinae, mrx47, l(2)04454, DmelCG1772, DmelCG17117, advanced, CIB1, p50, TCTP, antigen NY-CO-13, ACTFS, cell type cancer, Neoplasms, Kras2, p53, developmental stage, number, impaired, tumour stage, 143391_i_at, beta3 TU, protein-containing complex, pak3beta, hFat1, LFS1, presence, l(3)05745, NEOPL, cdi4, mrx30, p21Cip1, p21CIP1, CDHF7, polypeptide chain, resilient, 1700007J15Rik, tough, Clinical Progression, Cdi4, CDI4, DmF2, Low, anon-EST:Liang-2.13, BLC, Decapo, neoplasm, malignant tumour, SDI1, lod, vesica, Clinical, clone 2.13, D.m.BETA-60D, dysfunction, hdm2, tumour, UV96, CDKI, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), Trp53, NEEP21, Dac, Clinical Course, dacapo/cyclin-dependent kinase interactor 4, has or lacks parts of type, betaTub60C, Dap, beta3-tubulin, MRX47, beta[[3]]-tubulin, TRP53, MDM2, behaviour, CDK-interacting protein 1, Neoplastic Growth, Cancer, beta-Tub60D, Disease, HDMX, Dmbeta3, Dm-HTH, cancer of the bladder, cou, protein complex, malignant, BETA 60D, prac, beta3t, beta3-Tub, Trt, carcinoma of the urinary bladder, c-Ki-ras, ME5, Xp53, mereological quality, PAK3beta, Cip1), count in organism, neoplastic growth, Lr, MT, native protein, Bladder Detrusor Muscles, natural protein, XPak3, malignant neoplasm (disease), p53/tubulin, Protein, CG1772, beta[[3]] tubulin, Protein Cdkn1a, CDHR8, Relative Risk, CG33336, urocyst, primary cancer, Bladder, carcinoma bladder, 0610011M09Rik, Risks, D-p53, beta60C, AA415488, Dm-P53, l(3)86Ca, Cancers, Mdm-2, beta3, SIIR, Lds, disease of cellular proliferation, malignant tumor, dtl, Tub, Meis1, having decreased function, behavioural response to stimulus, bladder carcinoma, malignant neoplastic disease, Bladder Cancer, betatub60D, cardinality, Bra, quantitative, cancer of urinary bladder, NEOPLASMS BENIGN, Neoplasia, Bladder Detrusor Muscle, mda6, presence or absence in organismVasp, VASP, 907, DmelCG15112, ENHANCER OF ATNSI ACTIVITY, XXD, Data Set, 907 细胞, NICR1852., XD, Dhekelia, MENA, NDPP1, Eastern Sovereign Base Area, l(2)02029, Enb, enb, 907 cell, ENA, Ena, DHEKELIA, Dhekelia Sovereign Base Area, CG15112, ENA/VASP0.00.00.00.00.0falseena-DATASET-OBMDC-02-06-2014-16:18:34:907-525 - samplesWGS of 14 paired samples of Bladder Cancer patient2017-07-26 15:39:25EGAD0000100086596062477703527070462EGAS00001000738EGAC00001000186