Treatability across cancer subtypes

For each of the seven cancer subtypes in our dataset, this view shows what fraction of patients have a treatment route via an approved drug, a synthetic-lethal target, or both — and what fraction remain untreatable. The synthetic-lethal column is the gap PrecisionSL aims to fill.

Oncogene drug
Crossover (multi-route)
Synthetic lethal
Untreatable
What’s a hypermutator?

A hypermutator is a tumour sample with an unusually high mutation count — far more than is typical for its cancer subtype. In this dataset a sample is flagged when its z score is greater than 2 (more than two standard deviations above the cancer’s mean burden).

Biologically, hypermutators usually carry a defect that breaks DNA repair or proofreading — for example mismatch-repair deficiency (Lynch syndrome), POLE/POLD1 proofreading mutations, or APOBEC over-activity. The cell can’t correct replication errors, so mutations accumulate orders of magnitude faster than normal.

Clinically these are a distinct group: high mutation load creates many neoantigens, so hypermutators often respond well to immune checkpoint inhibitors (e.g. pembrolizumab, nivolumab). They sit outside the standard oncogene/SSL/untreatable framework but may have very effective alternative options.

PDAC Pancreatic ductal adenocarcinoma
69%
untreatable
1,183 patients
248 oncogene-treatable
34 crossover
81 SSL-treatable
820 untreatable
Median: 6 Range: 1–168 Hypermutators: 19 / 1183 (1.6%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in tumour suppressors (8)
  1. Transcriptional regulation by RUNX3
    4 genes FDR 8.6e-05
    SMAD4, ZFHX3, CDKN2A, TP53
  2. RUNX3 regulates CDKN1A transcription
    3 genes FDR 8.6e-05
    SMAD4, ZFHX3, TP53
  3. Generic Transcription Pathway
    4 genes FDR 0.08
    SMAD4, ZFHX3, CDKN2A, TP53
  4. RNA Polymerase II Transcription
    4 genes FDR 0.08
    SMAD4, ZFHX3, CDKN2A, TP53
  5. Gene expression (Transcription)
    4 genes FDR 0.09
    SMAD4, ZFHX3, CDKN2A, TP53
  6. SUMOylation of transcription factors
    2 genes FDR 0.15
    CDKN2A, TP53
  7. Defective Intrinsic Pathway for Apoptosis
    2 genes FDR 0.16
    CDKN2A, TP53
  8. Oncogene Induced Senescence
    2 genes FDR 0.16
    CDKN2A, TP53
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
OSCC Oesophageal squamous cell carcinoma
55%
untreatable
796 patients
238 oncogene-treatable
50 crossover
74 SSL-treatable
434 untreatable
Median: 9 Range: 1–56 Hypermutators: 40 / 796 (5.0%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in tumour suppressors (8)
  1. Transcriptional regulation by RUNX3
    3 genes FDR 0.047
    CDKN2A, EP300, TP53
  2. Regulation of TP53 Activity
    3 genes FDR 0.047
    CDKN2A, EP300, TP53
  3. SUMO E3 ligases SUMOylate target proteins
    3 genes FDR 0.047
    CDKN2A, EP300, TP53
  4. SUMOylation
    3 genes FDR 0.047
    CDKN2A, EP300, TP53
  5. Generic Transcription Pathway
    4 genes FDR 0.062
    KMT2D, CDKN2A, EP300, TP53
  6. RNA Polymerase II Transcription
    4 genes FDR 0.062
    KMT2D, CDKN2A, EP300, TP53
  7. Developmental Biology
    4 genes FDR 0.062
    KMT2D, CDKN2A, EP300, TP53
  8. PI5P Regulates TP53 Acetylation
    2 genes FDR 0.065
    EP300, TP53
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
OAC Oesophageal adenocarcinoma
47%
untreatable
281 patients
60 oncogene-treatable
52 crossover
38 SSL-treatable
131 untreatable
Median: 9 Range: 1–97 Hypermutators: 8 / 281 (2.8%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in oncogenes (1)
  1. Signaling by Receptor Tyrosine Kinases
    3 genes FDR 0.14
    ALK, ERBB4, NTRK3
Enriched in tumour suppressors (3)
  1. RUNX3 regulates CDKN1A transcription
    3 genes FDR 0.0021
    SMAD4, ZFHX3, TP53
  2. Transcriptional regulation by RUNX3
    4 genes FDR 0.0037
    SMAD4, ZFHX3, CDKN2A, TP53
  3. Developmental Biology
    6 genes FDR 0.091
    SMAD4, CDKN2A, ARID1A, TP53, EPHB1, EPHA3
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
GBM Glioblastoma (CNS astrocytoma grade IV)
42%
untreatable
947 patients
468 oncogene-treatable
59 crossover
27 SSL-treatable
393 untreatable
Median: 6 Range: 1–747 Hypermutators: 7 / 947 (0.7%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in oncogenes (8)
  1. Constitutive Signaling by EGFRvIII
    2 genes FDR 0.081
    PIK3CA, EGFR
  2. Signaling by EGFR in Cancer
    2 genes FDR 0.081
    PIK3CA, EGFR
  3. Signaling by ERBB2 KD Mutants
    2 genes FDR 0.081
    PIK3CA, EGFR
  4. Signaling by Ligand-Responsive EGFR Variants in Cancer
    2 genes FDR 0.081
    PIK3CA, EGFR
  5. Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
    2 genes FDR 0.081
    PIK3CA, EGFR
  6. Signaling by ERBB2 in Cancer
    2 genes FDR 0.081
    PIK3CA, EGFR
  7. Signaling by ERBB2 ECD mutants
    2 genes FDR 0.081
    PIK3CA, EGFR
  8. PI3K events in ERBB2 signaling
    2 genes FDR 0.081
    PIK3CA, EGFR
Enriched in tumour suppressors (8)
  1. Diseases of signal transduction by growth factor receptors and second messengers
    4 genes FDR 0.12
    RB1, PTEN, NF1, TP53
  2. Cell Cycle
    4 genes FDR 0.18
    RB1, CHEK2, ATRX, TP53
  3. Disease
    5 genes FDR 0.18
    RB1, ATRX, PTEN, NF1, TP53
  4. Formation of Senescence-Associated Heterochromatin Foci (SAHF)
    2 genes FDR 0.24
    RB1, TP53
  5. Regulation of TP53 Activity through Methylation
    2 genes FDR 0.24
    CHEK2, TP53
  6. Transcriptional Regulation by TP53
    3 genes FDR 0.24
    CHEK2, PTEN, TP53
  7. Generic Transcription Pathway
    4 genes FDR 0.24
    RB1, CHEK2, PTEN, TP53
  8. Oncogene Induced Senescence
    2 genes FDR 0.24
    RB1, TP53
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
SCLC Small cell lung carcinoma
32%
untreatable
245 patients
73 oncogene-treatable
63 crossover
31 SSL-treatable
78 untreatable
Median: 14 Range: 1–101 Hypermutators: 8 / 245 (3.3%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in tumour suppressors (8)
  1. Gene expression (Transcription)
    8 genes FDR 0.0036
    RB1, KMT2D, GRIN2A, KMT2C, PTEN, EP300, TP53, KDM6A
  2. Chromatin organization
    5 genes FDR 0.0036
    KMT2D, KMT2C, EP400, EP300, KDM6A
  3. Chromatin modifying enzymes
    5 genes FDR 0.0036
    KMT2D, KMT2C, EP400, EP300, KDM6A
  4. Formation of Senescence-Associated Heterochromatin Foci (SAHF)
    3 genes FDR 0.0046
    RB1, EP400, TP53
  5. Activation of anterior HOX genes in hindbrain development during early embryogenesis
    4 genes FDR 0.0046
    KMT2D, KMT2C, EP300, KDM6A
  6. Activation of HOX genes during differentiation
    4 genes FDR 0.0046
    KMT2D, KMT2C, EP300, KDM6A
  7. Generic Transcription Pathway
    7 genes FDR 0.0049
    RB1, KMT2D, GRIN2A, KMT2C, PTEN, EP300, TP53
  8. RNA Polymerase II Transcription
    7 genes FDR 0.0073
    RB1, KMT2D, GRIN2A, KMT2C, PTEN, EP300, TP53
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
LUSC Lung squamous cell carcinoma
31%
untreatable
677 patients
342 oncogene-treatable
87 crossover
36 SSL-treatable
212 untreatable
Median: 14 Range: 1–165 Hypermutators: 26 / 677 (3.8%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in oncogenes (8)
  1. Signaling by Receptor Tyrosine Kinases
    4 genes FDR 0.17
    PIK3CA, ERBB4, NTRK3, KDR
  2. Activated NTRK3 signals through PI3K
    2 genes FDR 0.18
    PIK3CA, NTRK3
  3. PI3K events in ERBB4 signaling
    2 genes FDR 0.18
    PIK3CA, ERBB4
  4. Erythropoietin activates Phosphoinositide-3-kinase (PI3K)
    2 genes FDR 0.18
    PIK3CA, PIK3CG
  5. PI3K events in ERBB2 signaling
    2 genes FDR 0.18
    PIK3CA, ERBB4
  6. Signaling by NTRK3 (TRKC)
    2 genes FDR 0.18
    PIK3CA, NTRK3
  7. Signaling by PDGFR in disease
    2 genes FDR 0.18
    PIK3CA, KDR
  8. Signaling by Erythropoietin
    2 genes FDR 0.18
    PIK3CA, PIK3CG
Enriched in tumour suppressors (8)
  1. Transcriptional regulation by RUNX3
    5 genes FDR 0.0012
    CREBBP, ZFHX3, CDKN2A, EP300, TP53
  2. Generic Transcription Pathway
    10 genes FDR 0.0012
    KMT2D, GRIN2A, CREBBP, ZFHX3, CDKN2A, KMT2C, PTEN, EP300, ARID1A, TP53
  3. RNA Polymerase II Transcription
    10 genes FDR 0.0018
    KMT2D, GRIN2A, CREBBP, ZFHX3, CDKN2A, KMT2C, PTEN, EP300, ARID1A, TP53
  4. Gene expression (Transcription)
    10 genes FDR 0.0034
    KMT2D, GRIN2A, CREBBP, ZFHX3, CDKN2A, KMT2C, PTEN, EP300, ARID1A, TP53
  5. Developmental Biology
    9 genes FDR 0.0094
    KMT2D, CREBBP, CDKN2A, KMT2C, EP300, ARID1A, TP53, EPHB1, EPHA3
  6. Zygotic genome activation (ZGA)
    3 genes FDR 0.0094
    CREBBP, EP300, TP53
  7. Transcriptional regulation by RUNX1
    5 genes FDR 0.01
    KMT2D, CREBBP, KMT2C, EP300, ARID1A
  8. Nuclear events mediated by NFE2L2
    4 genes FDR 0.011
    CREBBP, CDKN2A, EP300, KEAP1
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
LUAD Lung adenocarcinoma
24%
untreatable
1,013 patients
641 oncogene-treatable
107 crossover
22 SSL-treatable
243 untreatable
Median: 15 Range: 1–193 Hypermutators: 46 / 1013 (4.5%)
1 10 100 1k
Normal High burden (z > 2)
Enriched in oncogenes (8)
  1. Signaling by Receptor Tyrosine Kinases
    8 genes FDR 3.9e-06
    NTRK1, ERBB4, NTRK3, KDR, BRAF, KRAS, EGFR, MTOR
  2. Diseases of signal transduction by growth factor receptors and second messengers
    6 genes FDR 0.0013
    ERBB4, KDR, BRAF, KRAS, EGFR, MTOR
  3. Signal Transduction
    9 genes FDR 0.0036
    NTRK1, ERBB4, NTRK3, KDR, BRAF, KRAS, EGFR, MTOR, PIK3CG
  4. GRB2 events in ERBB2 signaling
    3 genes FDR 0.0036
    ERBB4, KRAS, EGFR
  5. Signaling by ERBB2 TMD/JMD mutants
    3 genes FDR 0.004
    ERBB4, KRAS, EGFR
  6. SHC1 events in ERBB2 signaling
    3 genes FDR 0.004
    ERBB4, KRAS, EGFR
  7. Signaling by NTRKs
    4 genes FDR 0.004
    NTRK1, NTRK3, BRAF, KRAS
  8. Signaling by ERBB2 KD Mutants
    3 genes FDR 0.0043
    ERBB4, KRAS, EGFR
Enriched in tumour suppressors (8)
  1. Generic Transcription Pathway
    10 genes FDR 0.0021
    KMT2D, GRIN2A, STK11, CREBBP, ZFHX3, KMT2C, ATM, ARID1A, TP53, SMARCA4
  2. RNA Polymerase II Transcription
    10 genes FDR 0.0024
    KMT2D, GRIN2A, STK11, CREBBP, ZFHX3, KMT2C, ATM, ARID1A, TP53, SMARCA4
  3. Gene expression (Transcription)
    10 genes FDR 0.0041
    KMT2D, GRIN2A, STK11, CREBBP, ZFHX3, KMT2C, ATM, ARID1A, TP53, SMARCA4
  4. Transcriptional regulation by RUNX1
    5 genes FDR 0.015
    KMT2D, CREBBP, KMT2C, ARID1A, SMARCA4
  5. TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
    3 genes FDR 0.015
    CREBBP, ATM, TP53
  6. Chromatin modifying enzymes
    5 genes FDR 0.015
    KMT2D, CREBBP, KMT2C, ARID1A, SMARCA4
  7. Chromatin organization
    5 genes FDR 0.015
    KMT2D, CREBBP, KMT2C, ARID1A, SMARCA4
  8. Developmental Biology
    8 genes FDR 0.044
    KMT2D, CREBBP, KMT2C, ARID1A, TP53, EPHB1, EPHA3, SMARCA4
Reactome enrichment via DAVID; FDR ≤ 0.25 cutoff, top hits by FDR ascending.
Across 5,142 patients in this dataset: 2,311 (45%) currently have no approved or known synthetic-lethal treatment route.
Patient cohort and treatment routes from the PrecisionSL analysis pipeline; underlying mutation data is from COSMIC.