Background
Methods
Data and normalization
Tumor genomic and patient datasets
Gene expression normalization
Gene-drug relationships
Therapy normalization
Defining eligible therapies for evaluation
Deriving the therapy efficacy model
Defining tumor genomics features
Defining rules from tumor genomic features
Validating the therapy efficacy model using survival analysis
Classifying patients using rules from tumor genomic features
Survival analysis models
#T | #E | #N | TSSa | Age | Sex | Stage | Grade | LIb | Smoke statusc | Tumor specificd | |
---|---|---|---|---|---|---|---|---|---|---|---|
GBM | 394 | 154 | 0 | ● | ● | ● | ● | ||||
OV | 573 | 262 | 0 | ● | ● | ● | ● | ● | ● | ||
BRCA | 905 | 817 | 104 | ● | ● | ● | ● | ||||
UCEC | 473 | 333 | 5 | ● | ● | ● | ● | ||||
KIRC | 505 | 470 | 65 | ● | ● | ● | ● | ● | |||
COAD | 424 | 192 | 0 | ● | ● | ● | ● | ● | ● | ||
READ | 168 | 71 | 0 | ● | ● | ● | ● | ● | ● | ||
BLCA | 139 | 96 | 13 | ● | ● | ● | ● | ● | |||
LUAD | 447 | 353 | 55 | ● | ● | ● | ● | ||||
LUSC | 404 | 220 | 16 | ● | ● | ● | ● | ||||
HNSC | 409 | 303 | 37 | ● | ● | ● | ● | ● | ● |
Results
Classification of therapies and patients using rules from tumor genomic features
Low-risk cohort | High-risk cohort | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
N | Age | Stage 1 or 2 | Stage 3 or 4 | Grade 1 or 2 | Grade 3 or 4 | N | Age | Stage 1 or 2 | Stage 3 or 4 | Grade 1 or 2 | Grade 3 or 4 | |
Any-Hit Model | ||||||||||||
GBM | 125 | 62 ± 13.3 | – | – | – | – | 9 | 52 ± 23.7 | – | – | – | – |
BRCA | 697 | 59 ± 13.3 | 533 | 164 | – | – | 118 | 53 ± 13.3 | 96 | 22 | – | – |
OV | 159 | 58 ± 10.4 | 9 | 150 | 17 | 142 | 103 | 57 ± 13.3 | 10 | 93 | 19 | 84 |
KIRC | 456 | 61 ± 13.3 | 389 | 67 | 211 | 245 | 14 | 58.5 ± 11.1 | 2 | 12 | 1 | 13 |
LUAD | 319 | 67 ± 10.4 | 246 | 73 | – | – | 10 | 62.5 ± 12.6 | 6 | 4 | – | – |
UCEC | 289 | 63 ± 10.4 | 226 | 63 | 164 | 125 | 44 | 61.5 ± 9.6 | 13 | 31 | 12 | 32 |
HNSC | 287 | 61 ± 11.9 | 136 | 151 | 199 | 78 | 16 | 56.5 ± 10.4 | 14 | 2 | 11 | 5 |
LUSC | 198 | 68.5 ± 8.2 | 152 | 46 | – | – | 14 | 65.5 ± 8.9 | 12 | 2 | – | – |
Therapy Efficacy Model | ||||||||||||
GBM | 127 | 61 ± 13.3 | – | – | – | – | 7 | 52 ± 23.7 | – | – | – | – |
BRCA | 776 | 58 ± 13.3 | 602 | 174 | 0 | 0 | 39 | 53 ± 13.3 | 27 | 12 | – | – |
OV | 228 | 58 ± 11.1 | 16 | 212 | 31 | 197 | 34 | 60.5 ± 11.9 | 3 | 31 | 5 | 29 |
KIRC | 463 | 61 ± 13.3 | 390 | 73 | 212 | 251 | 7 | 54 ± 8.9 | 1 | 6 | 0 | 7 |
LUAD | 321 | 67 ± 10.4 | 247 | 74 | 0 | 0 | 8 | 67 ± 10.4 | 5 | 3 | – | – |
UCEC | 310 | 63 ± 10.4 | 231 | 79 | 168 | 142 | 23 | 61 ± 10.4 | 8 | 15 | 8 | 15 |
HNSC | 288 | 61 ± 11.9 | 137 | 151 | 200 | 78 | 15 | 57 ± 13.3 | 13 | 2 | 10 | 5 |
LUSC | 202 | 68.5 ± 8.2 | 155 | 47 | 0 | 0 | 10 | 65 ± 8.9 | 9 | 1 | – | – |
Per-Cancer survival analysis
Univariateb | Multivariatec | |||
---|---|---|---|---|
HR [95% CI]a | p-value | HR [95% CI] | p-value | |
GBM | 0.87 [0.38, 2.01] | 7.5 × 10− 1 | 1.84 [1.17, 2.89] | 7.9 × 10− 3 |
BRCA | 1.96 [0.75, 5.12] | 1.7 × 10−1 | 1.80 [1.40, 2.30] | 3.0 × 10−6 |
OV | 1.56 [0.94, 2.57] | 8.4 × 10−2 | 1.46 [0.88, 2.42] | 1.4 × 10− 1 |
KIRC | 7.75 [3.25, 18.50] | 3.9 × 10− 6 | 3.07 [2.18, 4.33] | 1.7 × 10− 10 |
LUAD | 1.53 [0.47, 4.94] | 4.8 × 10−1 | 1.65 [0.94, 2.91] | 8.0 × 10− 2 |
UCEC | 1.60 [0.48, 5.32] | 4.4 × 10−1 | 0.94 [0.58, 1.54] | 8.1 × 10− 1 |
HNSC | 1.39 [0.63, 3.08] | 4.2 × 10−1 | 1.59 [1.05, 2.42] | 2.9 × 10−2 |
LUSC | 0.67 [0.21, 2.14] | 4.9 × 10−1 | 0.63 [0.35, 1.12] | 1.2 × 10−1 |
Pan-Cancer survival analysis
Univariate | Multivariate | |||||||
---|---|---|---|---|---|---|---|---|
Rulea | Genomics features | Low-risk (N) | High-risk (N) | High-risk (%) | HR [95% CI] | p-value | HR [95% CI] | p-value |
Export | 1 | 2749 | 109 | 3.8 | 1.49 [1.09, 2.05] | 1.2 × 10−2 | 1.49 [1.13, 1.96] | 4.7 × 10− 3 |
Import | 1 | 2777 | 81 | 2.8 | 0.90 [0.61, 1.33] | 6.0 × 10−1 | 1.00 [0.76, 1.32] | 1.0 × 100 |
Metabolism | 1 | 2642 | 216 | 7.6 | 1.26 [0.94, 1.69] | 1.3 × 10−1 | 1.12 [0.85, 1.48] | 4.2 × 10− 1 |
Metabolismb | 1 | 2809 | 49 | 1.7 | 1.74 [1.09, 2.77] | 2.1 × 10− 2 | 1.73 [1.31, 2.28] | 9.3 × 10− 5 |
Target | 1 | 2780 | 78 | 2.7 | 1.12 [0.76, 1.66] | 5.6 × 10− 1 | 1.07 [0.81, 1.41] | 6.3 × 10− 1 |
Any-Hit | 3 | 2530 | 328 | 11.5 | 1.21 [0.94, 1.55] | 1.4 × 10− 1 | 1.17 [0.88, 1.53] | 2.8 × 10− 1 |
Any-PK-Hit | 2 | 2660 | 198 | 6.9 | 1.26 [0.97, 1.64] | 7.8 × 10−2 | 1.27 [0.96, 1.67] | 9.4 × 10− 2 |
Efficacy Model | 2 | 2715 | 143 | 5.0 | 1.41 [1.06, 1.88] | 1.9 × 10−2 | 1.47 [1.11, 1.93] | 6.3 × 10− 3 |
Analysis of tumor genomics features
Therapy export
Ctype | Patient | Primary regimen | Additional therapy | Age | Stage | Grade | Detailsa | Target c | Metabolism | Transport |
---|---|---|---|---|---|---|---|---|---|---|
BRCA | TCGA-E2-A1LB | Cyclo-phosphamide Paclitaxel Doxorubicin Anti-Hormoneb | Trastuzumab | 41 | 2 | – | ER- | AKR1A1(3.01) - Dox | ABCC2(4.77) - Pac | |
BRCA | TCGA-E2-A158 | – | 43 | 2 | – | ER- | MAP2(−3.56) - Pac MAP4(− 3.29) - Pac | ABCC1(2.27) - Dox | ||
BRCA | TCGA-E2-A14V | Lapatinib | 53 | 2 | – | ER+ | EGFR(−4.65) - Lap | CYP2C8(2.2) - Pac | ||
BRCA | TCGA-AO-A0J3 | Fluorouracil Methotrexate | 67 | 2 | – | ER+ | MAP4(−3.11) - Pac | ABCC5(2.21) - 5FU,Meth FOLR1(− 3.42) - Meth | ||
BRCA | TCGA-BH-A0BA | – | 51 | 3 | – | ER+ | NQO1(3.22) - Dox | ABCC2(3.09) - Pac | ||
BRCA | TCGA-AO-A0JE | Trastuzumab | 53 | 3 | – | ER-Margin+ | ABCC1(2.73) - Pac, Dox ABCC2(3.86) - Pac, Dox | |||
OV | TCGA-09-0367 | Carboplatin Doc/Paclitaxel | Gemcitabine | 67 | 3 | 3 | LI + TRD+ | MAP2(−3.66) - Pac MAP4(−3.96) - Pac | NT5C(3.78) - Gem | SLC31A1(−2.67) - Car |
OV | TCGA-23-1123 | Doxorubicin | 59 | 3 | 3 | LI + TRD+ | NR1I2(3.42) - Pac | RALBP1(4.17) - Car,Dox | ||
OV | TCGA-24-1558 | Doxorubicin | 73 | 3 | 3 | TRD+ | MAP2(−4.71) - Pac,Doc | ABCC1(6.49) - Gem,Dox AABCC10(2.66) - Gem,Dox | ||
OV | TCGA-30-1860 | Doxorubicin | 58 | 3 | 3 | TRD+ | TOP2B(−4.39) - Pac,Dox MAP2(− 5.04) - Pac,Dox | |||
OV | TCGA-61-1724 | Doxorubicin Gemcitabine | 47 | 3 | 3 | LI+ | MAP2(−4.57) - Doc | DCTD(4.46) - Gem | ||
OV | TCGA-61-1741 | Tamoxifen | 76 | 3 | 3 | TRD+ | CYP2C8(3.19) - Pac,Tam NR1I2(3.94) - Pac,Tam | SLC31A1(−3.21) - Car | ||
KIRC | TCGA-CJ-4638 | Gemcitabine Fluorouracil | Bevacizumab | 46 | 4 | 4 | – | NT5C(3.84) UPB1(3.87) DPYS(2.33) - Gem,5FU | ||
LUAD | TCGA-50-5072 | Doc/Paclitaxel Carbo/Cisplatin | 74 | 3 | – | reformed smoker | ABCC2(5.12) - Doc,Pac | |||
UCEC | TCGA-AP-A052 | Carboplatin Paclitaxel | Gemcitabine | 59 | 4 | 3 | CMPK1(−4.12) - Gem | NR1I2(3.92) - Pac | ||
UCEC | TCGA-AP-A05D | 67 | 3 | 3 | MAPT(−3.05) - Pac TUBB1 (−2.43) - Pac | SLC31A1(− 3.7) - Carb | ||||
UCEC | TCGA-AP-A0LI | 67 | 3 | 3 | MAP2(−5.57) - Pac MAPT(−2.21) - Pac | SLC31A1(−4.11) - Carb | ||||
UCEC | TCGA-AX-A0IS | Gemcitabine Brivanib | 52 | 1 | 2 | MAP2(−3.09) - Pac MAP4(− 3.27) - Pac | DCTD(3.49) - Gem | |||
UCEC | TCGA-AX-A1CR | 70 | 2 | 3 | NR1I2(3.18) - Pac | SLC31A1(−5.04) - Carb | ||||
UCEC | TCGA-BS-A0TE | Doxorubicin Topotecan | 35 | 4 | 3 | AKR1C3(4.88) NQO1(3.68) NR2I1 (2.76) - Dox,Pac | ABCC2(5.22) - Top | |||
HNSC | TCGA-CR-7404 | Carboplatin Paclitaxel | Cepecitabine Cetuximab | 53 | 1 | – | never smoker | MAP2(−3.86) - Pac | ABCC5(5.08) - Cap | |
HNSC | TCGA-DQ-7589 | Docetaxel Fluorouracil | 70 | 1 | – | reformed smoker | ABCC1(5.83) - Doc,5FU,Pac ABCC5(4,74) - Coc,5FU,Pac | |||
LUSC | TCGA-46-6026 | Doc/Pacletaxel | Gemcitabine Paraplatin | 81 | 2 | – | reformed smoker | CMPK1(−3.05) - Gem | CYP2C8(3.02) - Pac NR1I2(3.86) - Pac | |
LUSC | TCGA-94-7033 | Cisplatin | 73 | 1 | – | reformed smoker | MAP4(−4.71) - Doc | SLC31A1(−3.26) - Cis |