Supplemental Figure 1: the Association Between Deleterious DDR (DNA Damage Response And

Supplemental Figure 1: The association between deleterious DDR (DNA damage response and repair) alteration status as determined by in silico analysis and (A) Progression-free survival and (B) overall survival, and the association between deleterious DDR alteration status as determined by literature review, and (C) progression-free survival and (D) overall survival. DDRwt: wild type DDR; DDRalt: altered DDR not considered deleterious per methodologies employed.

Supplemental Figure 2: Mutation load estimates based on MSK-IMPACT assay recapitulates whole exome sequencing data. Correlation between mutation counts generated from all sequences produced by TGCA bladder cancer whole exome sequencing and counts generated after first subsetting TCGA data to only those reads that coincide with the MSK-IMPACT capture regions.

Supplemental Figure 3: (A) Mean number of total mutations, (B) number of copy number alterations and (C) fraction of copy number altered genome based on number of DNA Damage Response and Repair (DDR) alterations. (Whisker plot with Tukey method)

Supplemental Figure 4: Influence of total mutation load on (A) Progression-free survival, (B) overall survival and (C) response rate. Total mutation load was divided into quartiles for the purpose of graphical representation.

Supplemental Table 1: DDR Gene Panel

Supplemental Table 2: All identified DDR alterations

Supplemental Table 1: DDR Gene Panel
MMR / NER / HR / FA / Checkpoint / Others
MLH1 / ERCC2 / BRCA1 / BRCA2 / ATM / POLE
MSH2 / ERCC3 / MRE11A / BRIP1 / ATR / MUTYH
MSH6 / ERCC4 / NBN / FANCA / CHEK1 / PARP1
PMS1 / ERCC5 / RAD50 / FANCC / CHEK2 / RECQL4
PMS2 / RAD51 / PALB2 / MDC1
RAD51B / RAD51C
RAD51D / BLM
RAD52
RAD54L
MMR: Mismatch repair, NER: Nucleotide excision repair, HR: Homologous recombination, FA: Fanconi anemia
Supplemental Table 2: Identified DDR Gene Alterations
Patient / Gene / AA change / Deleterious by Lit Review / Deleterious by in silico analysis / Type of Alterations
1 / MLH1 / P603R / 1 / 1 / Missense
2 / BRCA1 / E1541K / 0 / 0 / Missense
3 / ATR / E838Q / 0 / 1 / Missense
4 / BRCA1 / S1551C / 0 / 1 / Missense
ERCC4 / E210* / 1 / 1 / Nonsense
5 / ATM / R2618K / 0 / 0 / Missense
MSH6 / E171K / 0 / 0 / Missense
6 / BRCA2 / D2995N / 0 / 1 / Missense
7 / ATM / E2164Q / 1 / 1 / Missense
POLE / E2038K / 1 / 0 / Missense
8 / ATM / E38* / 1 / 1 / Nonsense
9 / POLE / E1213Q / 0 / 1 / Missense
MDC1 / R58* / 1 / 1 / Nonsense
10 / POLE / E537D / 1 / 1 / Missense
11 / NBN / NBN-intragenic / 1 / 1 / fusion
12 / BRCA1 / E1754Q / 0 / 1 / Missense
13 / ERCC2 / Y24C / 1 / 1 / Missense
14 / MDC1 / E148K / 0 / 1 / Missense
MDC1 / E177* / 1 / 1 / Nonsense
15 / FANCC / R361W / 0 / 1 / Missense
16 / ATM / R3008H / 1 / 1 / Missense
ATM / D2708N / 1 / 1 / Missense
NBN / R231H / 1 / 1 / Missense
17 / ERCC2 / R227H / 1 / 1 / Missense
18 / BRCA2 / D1769H / 0 / 1 / Missense
BRCA2 / D1923H / 0 / 1 / Missense
19 / CHEK2 / M1? / 1 / 1 / translation_start_site
20 / BRIP1 / E883K / 0 / 0 / Missense
BRIP1 / K940N / 0 / 0 / Missense
21 / NBN / E1417K / 0 / 0 / Missense
22 / BRCA2 / S611* / 1 / 1 / Nonsense
23 / BRCA2 / Q2858R / 0 / 1 / Missense
24 / MSH6 / P386Lfs*25 / 1 / 1 / FS del
BRCA2 / D946Rfs*13 / 1 / 1 / FS ins
ATM / C1674Y / 0 / 1 / Missense
ATM / Y1938H / 0 / 1 / Missense
ATM / C2337W / 0 / 1 / Missense
BLM / S1302F / 0 / 1 / Missense
BRCA1 / R841W / 1 / 0 / Missense
BRCA1 / N113K / 0 / 0 / Missense
BRCA1 / A1608T / 1 / 0 / Missense
BRCA2 / R448H / 0 / 0 / Missense
BRCA2 / Q1073H / 0 / 0 / Missense
BRCA2 / E1511K / 0 / 0 / Missense
CHEK2 / S50N / 1 / 1 / Missense
ERCC3 / R198H / 0 / 1 / Missense
ERCC3 / D386N / 0 / 1 / Missense
ERCC4 / L298I / 0 / 1 / Missense
ERCC5 / K64N / 0 / 1 / Missense
ERCC5 / E160K / 0 / 1 / Missense
ERCC5 / A21T / 0 / 0 / Missense
FANCC / S263Y / 0 / 1 / Missense
MDC1 / T1511I / 0 / 1 / Missense
MLH1 / L509I / 0 / 1 / Missense
MLH1 / L676F / 0 / 0 / Missense
MSH2 / Q419H / 0 / 1 / Missense
MSH6 / S614P / 0 / 0 / Missense
MSH6 / E810D / 0 / 0 / Missense
NBN / A46V / 0 / 1 / Missense
NBN / R1879C / 1 / 1 / Missense
NBN / R1878C / 0 / 1 / Missense
NBN / R579C / 0 / 1 / Missense
NBN / R1286C / 0 / 1 / Missense
NBN / P436H / 0 / 1 / Missense
PALB2 / L143M / 0 / 1 / Missense
RAD51C / E89K / 0 / 1 / Missense
RAD51D / G130D / 0 / 1 / Missense
RAD54L / H356Y / 0 / 0 / Missense
RECQL4 / A1159V / 1 / 1 / Missense
RECQL4 / R631C / 0 / 1 / Missense
ERCC3 / R325* / 1 / 1 / Nonsense
NBN / R114* / 1 / 1 / Nonsense
25 / BRCA2 / A1725_N1742delinsD / 1 / 1 / IF del
ERCC2 / N238S / 1 / 1 / Missense
ERCC4 / Y610* / 1 / 1 / Nonsense
26 / BRCA2 / L903F / 0 / 1 / Missense
ERCC2 / T49A / 1 / 1 / Missense
RAD51C / R168K / 0 / 1 / Missense
FANCA / MUTATED / 0 / 1 / Splice
27 / FANCA / K1299N / 0 / 1 / Missense
28 / ATR / X1237_splice / 1 / 1 / Splice
29 / RAD50 / T52I / 0 / 1 / Missense
RAD52 / R396C / 0 / 1 / Missense
30 / BRCA1 / C1382Y / 0 / 1 / Missense
31 / MLH1 / R725H / 1 / 1 / Missense
32 / ATM / R568I / 0 / 0 / Missense
33 / FANCA / S251L / 0 / 1 / Missense
MDC1 / A973V / 0 / 0 / Missense
PARP1 / S140F / 0 / 1 / Missense
PARP1 / P377S / 0 / 0 / Missense
34 / BRCA2 / N991D / 0 / 0 / Missense
BRCA1 / S713* / 1 / 1 / Nonsense
35 / RAD51C / V25* / 1 / 1 / FS del
36 / MDC1 / V711D / 0 / 0 / Missense
MSH6 / S261C / 0 / 1 / Missense
37 / CHEK1 / E310K / 0 / 0 / Missense
PALB2 / R414Q / 0 / 1 / Missense
38 / ATR / Q1422* / 1 / 1 / Nonsense
39 / ATM / D1853N / 1 / 0 / Missense
PMS2 / T597S / 1 / 0 / Missense
40 / ERCC5 / R959S / 0 / 1 / Missense
MLH1 / K618T / 1 / 1 / Missense
MLH1 / K618E / 1 / 1 / Missense
41 / ATM / D1853N / 1 / 0 / Missense
ATM / K988E / 0 / 0 / Missense
BRCA1 / M546I / 0 / 0 / Missense
MLH1 / K618T / 1 / 1 / Missense
MLH1 / K618E / 1 / 1 / Missense
RAD51C / H233R / 0 / 1 / Missense
ATM / Q1003* / 1 / 1 / Nonsense
42 / ATM / D1853N / 1 / 0 / Missense
BLM / P707S / 1 / 0 / Missense
BRCA2 / R2318Q / 1 / 1 / Missense
ERCC4 / P6L / 0 / 0 / Missense
ERCC5 / P19L / 0 / 1 / Missense
43 / ATM / D1853N / 1 / 0 / Missense
44 / ATM / L1901Wfs*16 / 1 / 1 / FS del
45 / ATM / F763L / 0 / 0 / Missense
ERCC2 / A306V / 0 / 1 / Missense
MSH2 / S153C / 0 / 1 / Missense
46 / ATM / HOMDEL / 1 / 1 / Homdel
47 / RAD51 / D12H / 0 / 0 / Missense