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BertolottoC Nature 2011 MITF SupplementaryInformation

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BertolottoC Nature 2011 MITF SupplementaryInformation
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  WWW.NATURE.COM/NATURE | 1 SUPPLEMENTARY INFORMATION  doi:10.1038/nature10539 Table S1. Frequency of the germline Mi-E318K    (c.952G>A) substitution in controls and in patients with melanoma only, according to melanoma type Subjects Number of non-carriers Number of carriers* Total Frequency of Mi-E318K FET p-value OR [95%CI] Controls   1649 10 1659 0.003 - Reference Patients with melanoma only 586 17 603 0.014 7.8 x 10 -5  4.78 [2.05-11.75] With family history 363 8 371 0.011 †  0.009 3.63[1.24-10.29] Without family history 223 9 232 0.019 †  1.7x 10 -4  6.65 [2.36-18.41 ] Patients with melanoma only 586   17   603   0.014 7.8 x 10 -5   4.78 [2.05-11.75]  Single melanoma   311   4   315   0.006 ††  0.26 2.12 [0.48-7.40]   Multiple melanomas 275 13 288 0.023 ††  3.91x10 -6  7.79 [3.12-20.04] * All carriers are heterozygotes for Mi-E318K. FET is the Fisher’s exact test for the difference in Mi-E318K allele frequency between each group of  patients and controls. OR (95% CI) is the odds-ratio (with 95% confidence interval) associated with the Mi-E318K carrier status. * Family history of melanoma and/or pancreatic cancer, FHM in Table S2; † The Mi-E318K allele frequency was not significantly different (p = 0.22; Fisher’s exact test) between  patients with melanoma that did/did not have a family history. ††  The Mi-E318K allele frequency was significantly different (p=0.02; Fisher’s exact test)    between  patients with a single melanoma and those with multiple primary melanomas, irrespective of family history.  SUPPLEMENTARY INFORMATION 2 | WWW.NATURE.COM/NATURE RESEARCH Table S2. Clinical and Pathological features of the 27 Mi-E318K    carriers ID Series †  Sex Type of 1 st  cancer ‡  Age at 1 st  cancer diagnosis, years Type of other cancers ‡  Age at other cancers diagnosis, years Family history of cancers §   19525 M+RCC M ccRCC 70 NM, LMM in situ 75, 76 None 20389 M+RCC M SSM 37 ccRCC 55 Maternal great uncle, CRC 10276 M+RCC M ccRCC 51 NM 62 Mother, UADT; maternal 1 st  cousin, lung 19034 M+RCC M ccRCC 69 NM 69 NA 24976 M+RCC M ccRCC 52 SSM 52 Mother, breast; maternal uncle, CRC; paternal uncle, leukaemia 10254 FHM F SSM 41 2 SSM + Lymphoma 53, 54, 55 Brother, CM; mother,  bladder; brother prostate 15168 ¥  FHM M NM 54 SSM 54 Father, CM; sister, CM; nephew, CM; first cousin OM (  MITF   WT) 23817 FHM F MM 60 - - Brother, CM 15012 FHM F SSM 33 - - Maternal first cousin, CM; Maternal aunt, NST+  breast; maternal uncle, CRC + BCC 22822 FHM F SSM 56 - - Brother, pancreatic cancer*; mother, uterine 21255 ¥  FHM F SSM 36 - - Sister: in situ CM 11311 ¥  FHM M SSM 40 2 SSM 54, 57 Maternal aunt, bladder; maternal first cousin: in situ CM; maternal grand-father, pancreatic 19063 FHM F LMM 53 LM 58 Maternal uncle, 2CM; maternal first cousin, CM 21000 MPM M NM 65 4 SSM 65, 65, 65, 66 Brother UADT; father UADT 23777 MPM F SSM 44 2 SSM, Breast 45, 45, 46 Father, RCC + seminoma 22112 MPM F SSM 39 In situ CM 40 None 22772 MPM M SSM 66 SSM 67 Maternal aunt, breast 22746 MPM M SSM 26 SSM 27 NA 21822 MPM M SSM 51 SSM 53 None 21281 MPM M SSM 59 SSM 59 Mother, leukaemia 20801 MPM F AM 36 CM 36 Father, CRC; mother, ovarian 25372 MPM M NM 62 SSM 63 Father, Lung; Paternal aunt, Leukemia 11473 RCC F jRCC 17 - - Mother, breast + melanoma (  MITF   WT) 21309 RCC F PRCC II 33 - - Mother, CM 21939 RCC M PRCC II 36 - - NA 25220 RCC F ccRCC 79 - - NA 26534 RCC F PRCC I 62 - - NA  WWW.NATURE.COM/NATURE | 3 SUPPLEMENTARY INFORMATION RESEARCH ¥ Pedigrees are shown in Figure S1a † M, melanoma; RCC, renal cell carcinoma; FHM, melanoma with family history of melanoma and/or  pancreatic cancer (see Methods); MPM, multiple primary melanomas. ‡ ccRCC, clear cell RCC; SSM, superficial spreading melanoma; NM, nodular melanoma; LMM, lentigo malignant melanoma; MM, mucosal melanoma; LM, lentigo maligna; jRCC, juvenile carcinoma t(X;17)(p11;q25); AM, acral melanoma; PRCC, papillary renal cell carcinoma. § CRC, colorectal cancer; UADT, upper aero-digestive tumour; NST, nervous system tumour; BCC,  basal Cell Carcinoma; RCC, renal cell carcinoma; OM, ocular melanoma; NA, not available. Table S3. Association analysis of Mi-E318K among patients with melanoma, renal cell carcinoma (RCC), or both cancers, and controls,   with and without adjusting for principal components (PCs) . † All carriers were heterozygotes for Mi-E318K. ‡The Wald test is a test of the effect of Mi-E318K carrier status on cancer risk using logistic regression, with and without adjusting for principal components (PCs). The PCs were estimated by a principal components analysis of genome-wide SNP data. § FET is the Fisher’s exact test for assessing whether the Mi-E318K allele frequency was significantly different between each group of patients and controls (this test does not adjust for principal components). ‼ OR (95% CI) is the odds-ratio (with 95% confidence interval) associated with the Mi-E318K carrier status. The odds-ratios were estimated by adjusting for principal components. Subjects Number of non-carriers Number of carriers †  Total Frequency of p.E.318K ❲  ld test p-value (adjusting for PCs) ‡   ❲  ld test p-value (not adjusting for PCs) ‡  FET p-value §  OR [95 % CI]   ‼  Controls 1380 9 1389 0.003 - - - Reference Melanoma and  ✴  or RCC patients 517 19 536 0.018 4.3 × 10 -5  2.2 × 10 -5  1.2 × 10 -5  5.41 [2.41-12.18] Melanoma + RCC 36 5 41 0.061 7.1 × 10 -7  1.5 × 10 -7  2.8 × 10 -5  20.34 [6.19-66.92] Melanoma only 424 11 435 0.013 4.1 × 10 -3  2.3 × 10 -3  2.6 × 10 -3  3.75 [1.52-9.24] RCC only 57 3 60 0.025 2.6 × 10 -3  2.1 × 10 -3  0.01 8.15 [2.08-31.96]  SUPPLEMENTARY INFORMATION 4 | WWW.NATURE.COM/NATURE RESEARCH Table S4: The Mi-E318K signature in RCC4 renal carcinoma cells. Changes in gene expression (Top22 up-regulated and top 10 down-regulated genes) induced by Mi-E318K compared to those induced by Mi-WT in RCC4 renal cell carcinoma cells. Fold Change p-value ID Entrez Gene Name 3.41 3.17E-02CCR7 chemokine (C-C motif) receptor 7 2.649 1.02E-03CLDN14 claudin 14 2.596 1.03E-04ADCY1 adenylate cyclase 1 (brain) 2.493 3.05E-03SLAMF7 SLAM family member 7 2.446 2.03E-02TRIM63 tripartite motif containing 63 2.262 1.69E-02HRK harakiri. BCL2 interacting protein (contains only BH3 domain) 2.09 8.88E-04ABCB5 ATP-binding cassette. sub-family B (MDR/TAP). member 5 1.954 3.21E-05ACSM3 acyl-CoA synthetase medium-chain family member 3 1.919 1.17E-04ITGBL1 integrin. beta-like 1 (with EGF-like repeat domains) 1.903 6.36E-03GADD45G growth arrest and DNA-damage-inducible. gamma 1.891 7.49E-04AICDA activation-induced cytidine deaminase 1.864 4.95E-03DMKN dermokine 1.852 2.33E-03BMP7 bone morphogenetic protein 7 1.831 1.03E-03SPINK1 serine peptidase inhibitor. Kazal type 1 1.78 3.73E-03AQP11 aquaporin 11 1.764 3.37E-05TRPV2 transient receptor potential cation channel. subfamily V. member 2 1.74 8.59E-03LY96 lymphocyte antigen 96 1.715 1.11E-05PPY pancreatic polypeptide 1.705 6.92E-06BAAT  bile acid CoA: amino acid N-acyltransferase (glycine N-choloyltransferase) 1.687 1.26E-03PLA1A phospholipase A1 member A 1.659 6.35E-03PNLIPRP3 pancreatic lipase-related protein 3 1.583 2.96E-04HSD17B6 hydroxysteroid (17-beta) dehydrogenase 6 homolog (mouse) -1.590 1.06E-09IRAK2 interleukin-1 receptor-associated kinase 2 -1.608 1.69E-03VCAM1 vascular cell adhesion molecule 1 -1.681 3.69E-03WNT5A wingless-type MMTV integration site family. member 5A -1.698 3.67E-03EDN2 endothelin 2 -1.712 2.11E-03IL6 interleukin 6 (interferon. beta 2) -1.933 1.68E-03AFAP1L2 actin filament associated protein 1-like 2 -1.972 2.52E-05HIST1H1D histone cluster 1. H1d -2.479 1.85E-02CXCL1 chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity. alpha) -2.700 2.29E-03SHISA2 shisa homolog 2 (Xenopus laevis) -3.721 1.32E-02EGR1 early growth response 1  WWW.NATURE.COM/NATURE | 5 SUPPLEMENTARY INFORMATION RESEARCH   Table S5: Genome-wide analysis of MITF binding with chromatin immunoprecipitation (top 40gene loci). The table gives the ratio of the read number determined for Mi-E318K/Mi-WT at thecorresponding genes in 501mel melanoma cells and the location of the peak relative to thetranscriptional start site (TSS). Chromosome gene_name ratio e318k/wt TSS_distance chr17 RNASEK 3.20-33chr13 FNDC3A 2.87-55chr17 GAA 2.77-69chr2 CYP20A1 2.73932chr12 STAT6 2.72-636chr19 ILVBL 2.7044chr11 PICALM 2.61-138chr16 RSPRY1 2.60-88chr1 SPOCD1 2.45-57chr12 VPS33A 2.32117chr19 DHPS 2.32101chr12 ERP29 2.27-35chr4 FAM13A 2.24-22chr16 CLN3 2.21-45chr17 LRRC48 2.2050chr8 XKR9 2.16-32chr12 BLOC1S1 2.1517chr22 HMOX1 2.14-193chr6 TNFAIP3 2.05-375chr19 BAX 1.98-105chr3 DIRC2 1.95-1178chr12 EIF4B 1.95105chr5 DUSP1 1.93-90chr7 VGF 1.92-320chr22 TOM1 1.89579chr19 PIAS4 1.87-103chr5 BTF3 1.85-1347chr16 CLCN7 1.8474chr9 UBAP2 1.84-214chr7 NUDCD3 1.81-50chr15 COMMD4 1.80-57chr11 USP28 1.80-235chr1 KLHL12 1.79-17chr17 AATF 1.79-101chr7 GET4 1.77-124chrX ZNF630 1.77-764chr11 RPUSD4 1.75-50chr1 ZMYND12 1.75203chr1 MTHFR 1.72-122chr3 CAPN7 1.72-2
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