Co-occurrence Analysis
190 gene-pair Fisher's exact tests, Benjamini-Hochberg FDR, quintuple search
Gene Pairs Tested
190
Significant (BH)
144
p<0.05 after correction
Mutual Exclusions
29
Strongest
FLT3+NPM1
O/E = 9.21
Quintuple Expected
7.7 × 10⁻¹³
1 in 1.3 trillion under independence
Co-occurrence Heatmap
Source: Fisher's exact test
31
[31] C 2013
Mutational landscape and significance across 12 major cancer types. Nature (2013)
, Benjamini-Hochberg FDR correction.
GENIE v19.0 17[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
, 20,820 myeloid samples.
Mutual exclusivity testing follows the pairwise-corrected estimate framework
30[30] S 2016
A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol (2016)
.
Color scale: log2(O/E). Blue = mutual exclusion, red = co-occurrence.
SETBP1 Co-mutation Landscape (OncoPrint)
Figure: SETBP1 co-mutation landscape.
271 SETBP1-mutated myeloid patients from GENIE v19.0
17
[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
.
Columns = patients (sorted by mutation count), rows = 20 myeloid driver genes.
Green = missense mutation. Patient's 5 genes highlighted in red.
Zero patients carry all five simultaneously.
Top Co-occurrences
| Gene Pair | Observed | Expected | O/E | p-value | BH q-value | Direction |
|---|---|---|---|---|---|---|
| FLT3 + NPM1 | 424 | 46.1 | 9.21 | < 1e-300 | < 1e-300 | Co-occurring |
| ASXL1 + SRSF2 | 729 | 226.5 | 3.22 | 1.22e-225 | < 1e-300 | Co-occurring |
| TET2 + SRSF2 | 741 | 244.0 | 3.04 | 1.32e-212 | < 1e-300 | Co-occurring |
| SRSF2 + RUNX1 | 554 | 151.4 | 3.66 | 2.75e-191 | < 1e-300 | Co-occurring |
| ASXL1 + RUNX1 | 701 | 235.5 | 2.98 | 1.72e-190 | < 1e-300 | Co-occurring |
| ASXL1 + EZH2 | 394 | 93.4 | 4.22 | 1.40e-166 | < 1e-300 | Co-occurring |
| DNMT3A + NPM1 | 443 | 118.0 | 3.75 | 1.24e-162 | < 1e-300 | Co-occurring |
| SRSF2 + IDH2 | 375 | 86.1 | 4.35 | 2.28e-153 | < 1e-300 | Co-occurring |
| ASXL1 + SETBP1 | 289 | 57.2 | 5.06 | 2.06e-151 | < 1e-300 | Co-occurring |
| ASXL1 + STAG2 | 344 | 79.5 | 4.33 | 1.43e-150 | < 1e-300 | Co-occurring |
| SRSF2 + STAG2 | 259 | 48.7 | 5.31 | 2.76e-127 | < 1e-300 | Co-occurring |
| RUNX1 + EZH2 | 276 | 62.4 | 4.42 | 9.23e-112 | < 1e-300 | Co-occurring |
| DNMT3A + FLT3 | 396 | 139.9 | 2.83 | 1.90e-94 | < 1e-300 | Co-occurring |
| TET2 + ASXL1 | 761 | 383.5 | 1.98 | 1.95e-94 | < 1e-300 | Co-occurring |
| RUNX1 + BCOR | 240 | 57.3 | 4.19 | 8.05e-91 | < 1e-300 | Co-occurring |
SETBP1 Partnerships
| Partner | Co-mutated | Expected | O/E | p-value | BH q-value | Direction |
|---|---|---|---|---|---|---|
| ASXL1 | 145 | 30.2 | 4.81 | 2.12e-72 | < 1e-300 | Co-occurring |
| SRSF2 | 79 | 20.2 | 3.90 | 4.06e-28 | < 1e-300 | Co-occurring |
| CBL | 32 | 6.3 | 5.08 | 2.11e-14 | < 1e-300 | Co-occurring |
| EZH2 | 36 | 8.5 | 4.24 | 1.18e-13 | < 1e-300 | Co-occurring |
| CSF3R | 18 | 1.8 | 9.93 | 1.38e-13 | < 1e-300 | Co-occurring |
| U2AF1 | 39 | 10.7 | 3.64 | 1.36e-12 | < 1e-300 | Co-occurring |
| RUNX1 | 39 | 19.1 | 2.04 | 1.58e-5 | 7.40e-5 | Co-occurring |
| NRAS | 29 | 12.9 | 2.26 | 3.31e-5 | 1.37e-4 | Co-occurring |
| JAK2 | 14 | 31.9 | 0.44 | 2.16e-4 | 7.91e-4 | Exclusive |
| PTPN11 | 15 | 5.8 | 2.60 | 6.90e-4 | 0.0023 | Co-occurring |
| NPM1 Depleted | 2 | 12.1 | 0.17 | 7.87e-4 | 0.0024 | Exclusive |
| GATA2 | 11 | 4.1 | 2.67 | 0.0028 | 0.0076 | Co-occurring |
| IDH1 Depleted | 1 | 7.5 | 0.13 | 0.0075 | 0.0191 | Exclusive |
| TP53 | 14 | 24.6 | 0.57 | 0.0225 | 0.0531 | Exclusive |
| SMC3 | 4 | 1.2 | 3.38 | 0.0300 | 0.0661 | Co-occurring |
| BCORL1 | 0 | 3.8 | 0.00 | 0.0348 | 0.0719 | Exclusive |
| STAG2 | 11 | 6.3 | 1.74 | 0.0644 | 0.1251 | Co-occurring |
| DDX41 | 2 | 0.4 | 4.59 | 0.0691 | 0.1266 | Co-occurring |
| WT1 | 3 | 6.8 | 0.44 | 0.1664 | 0.2855 | Exclusive |
| RAD21 | 4 | 2.2 | 1.84 | 0.1730 | 0.2855 | Co-occurring |
| SF3B1 | 8 | 13.1 | 0.61 | 0.1918 | 0.3014 | Exclusive |
| CALR | 4 | 7.3 | 0.55 | 0.2548 | 0.3822 | Exclusive |
| ZRSR2 | 6 | 4.0 | 1.49 | 0.3014 | 0.4325 | Co-occurring |
| CEBPA | 2 | 4.4 | 0.46 | 0.3303 | 0.4542 | Exclusive |
| SMC1A | 0 | 1.2 | 0.00 | 0.6334 | 0.8293 | Exclusive |
| FLT3 | 10 | 11.9 | 0.84 | 0.6534 | 0.8293 | Exclusive |
| DNMT3A | 30 | 28.3 | 1.06 | 0.6853 | 0.8376 | Co-occurring |
| BCOR | 9 | 8.0 | 1.12 | 0.7141 | 0.8417 | Co-occurring |
| TET2 | 34 | 35.5 | 0.96 | 0.8534 | 0.9711 | Exclusive |
| KRAS | 8 | 8.3 | 0.96 | 1.0000 | 1.0000 | Exclusive |
| IDH2 | 12 | 12.4 | 0.96 | 1.0000 | 1.0000 | Exclusive |
| MPL | 3 | 3.5 | 0.86 | 1.0000 | 1.0000 | Exclusive |
| PHF6 | 5 | 5.2 | 0.97 | 1.0000 | 1.0000 | Exclusive |
IDH1 depletion (O/E=0.13) and
NPM1 depletion (O/E=0.17) stand out as the strongest
mutual exclusions with SETBP1 mutations
1
[1] R 2013
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013)
2[2] H 2013
Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013)
.
This is biologically consistent:
SETBP1-mutant clones occupy a distinct ontogenetic niche
(MDS/MPN overlap, CNL, aCML) where NPM1 mutations are rare and
IDH1 mutations preferentially co-occur with NPM1 in AML
12[12] E 2016
Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med (2016)
.
The strongest positive associations are
CSF3R (O/E=9.93, p=1.4 × 10−13)
and ASXL1 (O/E=4.81, p=2.1 × 10−72), reflecting the classical CNL/aCML genotype.
The IDH1+SETBP1 depletion (O/E=0.13) is consistent with
SETBP1's role as an epigenetic hub
3
[3] R 2018
SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Commun (2018)
, where mutant SETBP1 drives
transcriptional deregulation via HCF1/KMT2A interaction and PP2A
inhibition. Redundant epigenetic disruption through IDH1-mediated DNA
hypermethylation appears to be negatively selected when SETBP1 already
provides broad chromatin remodeling. This functional overlap explains the
mutual exclusivity: clones carrying both mutations gain no additional
fitness advantage, so the combination is purged by clonal competition.
Quintuple Co-occurrence Analysis
The quadruple analysis assumed four driver mutations. With EZH2 V662A
reclassified from VUS to Pathogenic (5/5 computational models
concordant, EVE 0.9997), this becomes a quintuple co-occurrence
search. The expected frequency drops from 1.13e-4 to
7.7 × 10−13, over a billion times rarer.
EZH2 V662A has 0 carriers in the entire GENIE v19.0
17
[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
myeloid cohort (0/20,739). The variant
itself does not exist in the database, making any multi-gene search
involving this specific variant a guaranteed zero. Under a statistical
independence assumption 30[30] S 2016
A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol (2016)
, the
probability of all five specific variants (DNMT3A R882H + IDH2 R140Q
+ SETBP1 G870S 1[1] R 2013
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013)
2[2] H 2013
Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013)
+ PTPN11 E76Q + EZH2 V662A) co-occurring in a single myeloid patient
is approximately 7.7 × 10−13, roughly
1 in 1.3 trillion. Even if all 8 billion humans had
myeloid cancer, this profile would still be unique, 162 times over.
| Combination | Observed | Expected | Notes |
|---|---|---|---|
| DNMT3A p.R882H + IDH2 p.R140Q + SETBP1 p.G870S | 0 | ~0.21 | No triple match in GENIE |
| DNMT3A p.R882H + IDH2 p.R140Q + PTPN11 p.E76Q | 0 | ~0.02 | No triple match in GENIE |
| DNMT3A p.R882H + SETBP1 p.G870S + PTPN11 p.E76Q | 0 | ~0.00 | No triple match in GENIE |
| IDH2 p.R140Q + SETBP1 p.G870S + PTPN11 p.E76Q | 0 | ~0.00 | No triple match in GENIE |
| All four variants (original) | 0 | ~0.000 | Expected: 1.13e-4 |
| EZH2 V662A (fifth driver) | 0 | 0 | 0/20,739 carriers; variant absent from GENIE |
| Gene-level quintuple (any variant) | 0 | 0.0034 | Any DNMT3A+IDH2+SETBP1+PTPN11+EZH2 variant |
| All five specific variants | 0 | 7.7 × 10−13 | 1 in 1.3 trillion under independence |
Source: Expected values calculated under
independence assumption 30
[30] S 2016
A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol (2016)
:
P(quint) = P(DNMT3A R882H) x P(IDH2 R140Q) x P(SETBP1 G870S) x
P(PTPN11 E76Q) x P(EZH2 V662A).
Individual variant frequencies from GENIE v19.0
17[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
myeloid panel-eligible cohort
(N=21,017 myeloid,
N=18,625 panel-eligible for original four).
EZH2 V662A frequency = 0/20,739.
Gene-level quintuple uses gene-level (any coding variant) frequencies.
References
- Piazza R et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013). PubMed
- Makishima H et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013). PubMed
- AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov (2017). DOI
- Kandoth C et al. Mutational landscape and significance across 12 major cancer types. Nature (2013). PubMed
- Canisius S et al. A novel independence test for somatic alterations in cancer. Genome Biol (2016). DOI
- Papaemmanuil E et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med (2016). PubMed
- Piazza R et al. SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Commun (2018). PubMed