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Supplementary Fig S1 Tumour Mutation Burden

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Supplementary Fig S1 Tumour Mutation Burden Supplementary Figures & Legends Meta-Analysis and Systematic Review of the Genomics of Mucosal Melanoma Natasa Broit1,2, Peter A. Johansson1, Chloe B. Rodgers3, Sebastian T. Walpole1, Felicity Newell1, Nicholas K. Hayward1, Antonia L. Pritchard1, 3 *** Supplementary Fig. S1 | Tumour mutation burden and its association with mutations in DNA repair genes. Mutations in two or more DNA repair genes (other than TP53) were associated with a significant increase in tumour mutation burden (Kendall’s Tau Test: p = 0.00003). Mutations in TP53 have previously been reported to be associated with an increase in tumour mutation burden, however a significant association in this cohort was not seen (Mann-Whitney Test: p = 0.98846). Colors are indicative of the number of DNA repair mutations, i.e. gray = no mutations, red = ≥3 DNA repair mutations, orange = 2 DNA repair mutations, yellow = 1 DNA repair mutation. Tumors with TP53 mutations are indicated by a bolded asterix above each column bar. Supplementary Fig. S2 | Mutation Signature Analysis A. Proportions of signatures detected in individual tumors. Signatures represented across the cohort commonly included SBS39 (unknown aetiology), SBS1 (aetiology associated with deamination of 5-methylcytosine to thymine) and SBS7a/b (aetiology associated with exposure to ultraviolet light). B. Mutation signatures identified in samples stratified by primary site. A round dot represents the detection of a signature in the primary site. Shading is indicative of the mean signature burden across all samples of the indicated primary site. Signatures with a mean representation of < 5% are not displayed. Supplementary Fig. S3 | Genes significantly altered by copy number alterations. GISTIC analysis was performed to identify regions with significantly recurrent chromosomal copy loss (left) and gain (right) in the main cohort. Cancer genes of interest are marked alongside loci peaks. Supplementary Fig. S4 | Further mutations in genes encoding ligands and receptors. A. Mutations in genes encoding ligands and receptors in the main cohort (n = 173). B. Mutations, copy number alterations and structural variants (if reported) in genes encoding ligands and receptors in the main cohort (n = 72) Supplementary Fig. S5 | Further mutations in genes encoding components of cytoplasmic signaling (multiple pathways). A. Mutations in genes encoding components of cytoplasmic signaling in the main cohort (n = 173). B. Mutations, copy number alterations and structural variants (if any reported) in genes encoding components of cytoplasmic signaling in the main cohort (n = 72). Supplementary Fig. S6 | Further mutations in genes encoding components of the cell cycle. A. Mutations in genes encoding components of the cell cycle in the main cohort (n = 173). B. Mutations, copy number alterations and structural variants (if any reported) in genes encoding components of the cell cycle in the main cohort (n = 72). Supplementary Fig. S7 | Further mutations in genes encoding components of the DNA repair pathways. A. Mutations in genes encoding genes involved in DNA repair pathways in the main cohort (n = 173). B. Mutations, copy number alterations and structural variants (if any reported) in genes involved in DNA repair pathways in the main cohort (n = 72). Supplementary Fig. S8 | Further mutations in genes encoding proteins involved in chromatin modifications. A. Mutations in genes encoding genes involved in chromatin modification in the main cohort (n = 173). B. Mutations, copy number alterations and structural variants (if any reported) in genes involved in chromatin modification in the main cohort (n = 72). SN24 OC46 OC36 Supplementary Fig. S1 OC35 OC13 OC25 OC66 VV21 OC69 OC28 OC9 OC49 OC30 OC59 OC52 OC98 OC2 AR6 OC75 OC37 * VV8 VV23 VV6 OC87 OC58 SN22 OC71 OC14 AR16 VV22 * VV16 VV11 SN23 OC85 OC51 VV14 OC57 SN9 * SN13 SN12 OC39 SN6 OC8 E1 VV7 VV5 VV10 OC97 OC79 OC43 AR4 VV13 VV12 SN17 OC94 SN15 OC93 OC78 AR15 AR11 VV1 SN21 SN11 OC7 U2 SN20 OC3 VV9 OC24 AR9 VV15 OC12 AR5 SN2 OC6 AR2 VV2 OC73 OC54 OC82 OC77 OC56 OC26 AR10 U3 OC81 OC19 U1 OC18 OC86 OC61 VV3 OC96 OC17 OC1 SN16 SN7 OC53 OC15 OC65 OC40 OC21 SN18 SN1 * OC32 * OC44 OC34 SN3 OC88 OC60 AR3 OC92 OC50 * OC22 OC4 OC38 OC63 SN10 AR7 OC90 OC70 OC47 OC95 OC41 E2 AR1 OC5 SN28 OC72 * OC48 AR8 VV4 OC91 OC64 OC80 SN8 OC23 OC10 SN4 OC89 OC83 OC16 OC62 SN5 OC11 OC67 SN14 OC84 P1 SN19 SN25 OC45 OC20 AR12 OC74 VV17 OC29 SN27 OC76 OC33 ≥ 3 DNA repair gene mutations OC68 VV18 AR13 2 DNA repair gene mutations U4 OC27 VV19 1 DNA repair gene mutation OC55 OC42 VV20 AR14 SN26 OC31 * O1 0 200 400 600 800 Non-Synonymous Mutation Count A Supplementary Fig. S2 B Primary Site Eye Anorectal Penile Unknown Signature Oral Cavity Sinonasal Esophagus Vulvovaginal (n = 2) (n = 98) (n = 28) (n = 1) (n = 23) (n = 16) (n = 1) (n = 4) SBS1 SBS3 SBS4 SBS5 SBS7a SBS7b SBS8 SBS18 s e l p SBS19 m a S SBS25 SBS30 SBS24 SBS29 SBS8 SBS37 SBS6 SBS5 SBS38 SBS46 SBS40 SBS39 SBS32 SBS40 SBS29 SBS38 SBS44 SBS16 SBS12 SBS57 SBS1 SBS39 SBS58 SBS7b Signature contribution < 5% SBS7a Signature contribution 5 – 20 % Other Signature contribution 20 – 35 % 0 0 0 0 0 0 2 4 6 8 0 1 % Signature Proportion Supplementary Fig. S3 Deletion Amplification 0.8 0.4 0.2 0.15 0.1 0.1 0.45 0.8 ARID1A 1 MITF 3 KIT TERT, SKP2 5 ARID1B 7 BRAF CDKN2A 9 PTEN CCND1, YAP, GAB2 ATM 11 CDK4, MDM2 13 SPRED1 15 NF1 17 19 21 −30 −10 −8 −4 −2 Chr −20 10 10 10 10 10 0.1 0.1 10−2 10−3 10−6 10−10 10 Supplementary Fig. S4 0 33 A KIT 19% CBL 4% NEURL 3% ERBB4 3% ERBB2 1% FGFR2 1% FGFR4 1% EFNA1 1% EGFR 1% FGFR1 1% FGFR3 1% IGF2R 1% DLL3 1% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Missense Mutation Frameshift Deletion Oral Cavity Unknown Unknown Inframe Insertion Splice Site Mutation Sinonasal Eye Upper Inframe Deletion Anorectal Esophagus Lower Vulvovaginal Penile B 0 26 CBL 36% IGF2R 36% KIT 26% FGFR3 21% FGF3 18% FGF4 18% FGF19 18% PDGFRA 18% FGFR1 15% ERBB2 15% WNT11 14% NEURL1 14% EFNA1 11% EFNA3 11% EFNA4 11% FGFR4 11% ERBB4 11% WNT3A 8% WNT9A 8% DLL3 6% EGFR 4% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Missense Mutation Amplification Oral Cavity Unknown Unknown Splice Site Mutation Structural Variant (LoF) Sinonasal Eye Upper Inframe Deletion Complex Event Anorectal Esophagus Lower Loss of Heterozygosity Vulvovaginal Penile Supplementary Fig. S5 A 0 17 NF1 10% BRAF 9% NRAS 9% CTNNB1 5% SPRED1 4% MAP4K4 4% HRAS 2% PTEN 2% TSC2 2% NOTCH2 2% LATS2 2% KRAS 1% PIK3CG 1% TSC1 1% NOTCH3 1% NOTCH4 1% PIK3C2B 1% AKT3 1% APC 1% GSK3B 1% NOTCH1 1% MAP2K1 1% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Frameshift Insertion Inframe Deletion Oral Cavity Unknown Unknown Missense Mutation Nonsense Mutation Sinonasal Eye Upper Frameshift Deletion Multi Hit Anorectal Esophagus Lower Splice Site Mutation Vulvovaginal Penile B 0 26 NF1 36% LATS1 32% NRAS 28% YAP1 28% BRAF 26% PTEN 26% SPRED1 21% GAB2 21% HRAS 14% BTRC 14% TSC1 12% LATS2 12% GSK3B 11% CTNNB1 11% PIK3CG 10% PIK3C2B 10% KRAS 8% AKT3 8% TSC2 8% MAP4K4 8% APC 7% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Frameshift Insertion Homozygous Deletion Oral Cavity Unknown Unknown Missense Mutation Loss of Heterozygosity Sinonasal Eye Upper Frameshift Deletion Amplification Anorectal Esophagus Lower Splice Site Mutation Structural Variant (LoF) Vulvovaginal Penile Inframe Deletion Complex Event Nonsense Mutation Supplementary Fig. S6 A 0 8 TP53 5% ATR 2% MDM2 2% RB1 2% ATM 2% CDKN2A 2% CHEK2 1% SKP2 1% CDK4 1% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Missense Mutation Frameshift Insertion Oral Cavity Unknown Unknown Nonsense Mutation Inframe Insertion Sinonasal Eye Upper Splice Site Mutation Anorectal Esophagus Lower Frameshift Deletion Vulvovaginal Penile B 0 41 CDKN2A 57% ATM 38% CHEK1 33% CDK4 24% MDM2 22% TP53 18% CCND1 18% SKP2 15% ATR 14% CHEK2 14% MYC 12% RB1 12% CDK6 10% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Nonsense Mutation Loss of Heterozygosity Oral Cavity Unknown Unknown Missense Mutation Amplification Sinonasal Eye Upper Splice Site Mutation Structural Variant (LoF) Anorectal Esophagus Lower Frameshift Deletion Complex Event Vulvovaginal Penile Homozygous Deletion Supplementary Fig. S7 A 0 14 TDG 8% ATR 2% ATM 2% MSH3 2% POLD1 2% PRKDC 2% CHEK2 1% MSH4 1% MSH6 1% PMS1 1% NEIL1 1% POLE 1% DDB1 1% MDC1 1% RAD51 1% PALB2 1% BRIP1 1% MLH3 1% MSH2 1% PMS2 1% MPG 1% DDB2 1% RBX1 1% PARP1 1% CUL4A 1% CUL4B 1% XPC 1% RAD23B 1% ERCC3 1% ERCC5 1% MRE11A 1% BRCA2 1% DCLRE1C 1% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Inframe Insertion Nonsense Mutation Oral Cavity Unknown Unknown Missense Mutation Frameshift Insertion Sinonasal Eye Upper Frameshift Deletion Inframe Deletion Anorectal Esophagus Lower Splice Site Mutation Vulvovaginal Penile B 0 27 ATM 38% CHEK1 33% GTF2H5 33% NEIL2 25% RAD51 18% DCLRE1C 18% POLD3 17% ERCC6 17% MDC1 17% ATR 14% CHEK2 14% MSH5 12% NEIL3 12% MBD4 12% POLB 12% POLE 12% POLE3 12% GTF2H4 12% BRCA2 12% PMS2 11% OGG1 11% UNG 11% MUTYH 11% TDG 11% PCNA 11% POLE2 11% DDB2 11% CUL4A 11% GTF2H3 11% ERCC5 11% PARP1 11% PRKDC 11% NEIL1 10% RAD23B 10% BRIP1 10% MLH3 8% MPG 8% POLD1 8% GTF2H1 8% RAD50 8% BRCA1 8% XRCC5 8% NHEJ1 8% MSH3 7% MSH4 7% NTHL1 7% SMUG1 7% APEX1 7% XPC 7% MNAT1 7% CDK7 7% MLH1 6% POLD2 6% POLD4 6% DDB1 6% GTF2H2 6% ERCC2 6% PALB2 6% BARD1 6% XRCC4 6% XRCC6 6% PMS1 4% RBX1 4% ERCC8 4% CCNH 4% ERCC4 4% MSH2 3% MSH6 3% ERCC3 3% POLE4 1% Primary Site Primary Region Alteration Classification Primary Sites Primary Region Inframe Insertion Loss of Heterozygosity Oral Cavity Unknown Unknown Missense Mutation Homozygous Deletion Sinonasal Eye Upper Splice Site Mutation Structural Variant (LoF) Anorectal Esophagus Lower Inframe Deletion Complex Event Vulvovaginal Penile Amplification Supplementary Fig.
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