Genomic Co-occurrence Analysis: DNMT3A R882H / IDH2 R140Q / SETBP1 G870S / PTPN11 E76Q / EZH2 V662A in Myeloid Malignancies

Røine, Henrik G.

DDX41+SETBP1 Deep Dive

Germline/somatic DDX41 co-occurrence with SETBP1 in myeloid neoplasms

DDX41+SETBP1 co-occurrence analysis across GENIE v19.0 myeloid patients. DDX41 germline mutations define a distinct myeloid neoplasm subtype. This page examines their overlap with SETBP1 somatic mutations in the context of a five-driver mutation profile.

DDX41+SETBP1

2 patients

O/E=4.59, p=0.069

DDX41 Coverage

16 panels

~3,522 myeloid samples covered

BH q-value

0.570

Not significant after correction

Novel Variants

2

EZH2 V662A (0 PubMed) + PTPN11 E76Q (2 PubMed)

Five-Driver Context

The EZH2 V662A reclassification from VUS to Pathogenic (5/5 models concordant, EVE 0.9997) elevates the DDX41+SETBP1 co-occurrence finding. The index patient carries five confirmed driver mutations, not four. The quintuple expected frequency is ~7.7×10^-13, over a billion times rarer than the quadruple.

ClinGen Gene-Disease Validity

Gene	Disease	Validity	Classification Date
DNMT3A	AML	Definitive	2017
IDH2	AML	Definitive	2017
SETBP1	MDS	Definitive	2019
PTPN11	JMML/AML	Definitive	2018
EZH2	MDS	Strong	2020
DDX41	Myeloid neoplasm	Definitive	2022

All 6 genes (5 drivers + DDX41) have Definitive or Strong ClinGen validity. This confirms that every mutated gene in this profile is an established myeloid driver.

DDX41+SETBP1 Co-occurrence

DDX41 germline mutations ^{7[7] C 2015
Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell (2015)
PubMedDOI}^{6[6] H 2023
Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood (2023)
PubMedDOI} are an active area of myeloid neoplasm research. DDX41-mutant MN defy current prognostic schemes ^{8[8] C 2026
DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system. Leukemia (2026)
PubMedDOI}. This analysis found 2 co-mutated patients with SETBP1 mutations ^{2[2] H 2013
Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013)
PubMedDOI}^{1[1] R 2013
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013)
PubMedDOI} in GENIE v19.0 ^{17[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
PubMedDOI} across 3,522 eligible samples. Both genes were on the sequencing panel in ~3,522 samples (16 panels). The co-occurrence has O/E=4.59, Fisher's exact p=0.069, BH-adjusted q=0.570. All patients are from UHN (Toronto), both AML, and both share EZH2 as an additional co-mutated gene.

Patient ID	Cancer Type	DDX41 Mutation	SETBP1 Mutation	Other Genes	Total Mutations
GENIE-UHN-LIB166087-001	AML	p.G402W + p.M1?	p.G870S (SKI)	ASXL1/CBL/DNMT3A/EZH2/RUNX1	8
GENIE-UHN-LIB989414-001	AML	p.Q329Rfs*7	p.N454D (non-SKI)	EZH2	3

Note: Both patients from University Health Network (Toronto). Both AML. Both share EZH2 co-mutation.

PTPN11 E76Q Knowledge Gap

Semantic Scholar search across all 6 patient variant queries returned 144 unique publications. Type 1 progression mutations (PTPN11, IDH2) ^{15[15] H 2017
Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017)
PubMedDOI} are key to clonal evolution. Yet PTPN11 E76Q returned only 2 publications, the fewest of any variant queried. By comparison, DNMT3A R882H returned 89 and IDH2 R140Q returned 67. This variant is significantly understudied relative to its clinical significance: E76Q is a recurrent activating mutation in the SHP2 phosphatase domain, found in both de novo and therapy-related myeloid neoplasms.

Patient 2642: Closest Match

Patient 2642 is the only patient in GENIE v19.0 ^{17[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
PubMedDOI} with IDH2 R140Q + PTPN11 E76Q + SETBP1 G870S (triple co-occurrence). This is the closest match to the index patient's quadruple profile, missing only DNMT3A R882H. Found in 1 out of 21,017 myeloid patients. No patient in any database has all four mutations. With EZH2 V662A now reclassified as a fifth driver, the gap widens further: Patient 2642's EZH2 status is unknown (not reported), making this closest match even less close to the full quintuple profile. Clonal succession ^{15[15] H 2017
Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017)
PubMedDOI} modeling and IPSS-M ^{13[13] E 2022
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022)
PubMedDOI} scoring would both be needed to fully characterize this case.

Property	Value
Patient ID	2642
Matching mutations	IDH2 R140Q, PTPN11 E76Q, SETBP1 G870S
Missing from quadruple	DNMT3A R882H
Database	GENIE v19.0
Denominator	21,017 myeloid patients
Frequency	1 / 21,017 (0.005%)

Note on DDX41 Numbers

The earlier analysis (32-gene filter, 271 SETBP1 patients) found 3 co-mutated patients with O/E=5.16, p=0.020. The later analysis (225 SETBP1 patients) found 2 patients with O/E=4.59, p=0.069. The difference is likely due to different hypermutation filter thresholds: the first run used a >20 coding mutation cutoff while the second used a stricter filter that excluded one additional patient.

Analysis	SETBP1 Patients	DDX41+SETBP1	O/E	p-value	BH q-value
32-gene filter	271	3	5.16	0.020	0.041
Refined filter	73	2	4.59	0.069	NS

References

Polprasert C, Schulze I, Sekeres MA, Makishima H, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell (2015). PubMed
Makishima H, Saiki R, Nannya Y, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood (2023). PubMed
Gurnari C, Makishima H, Durmaz A, et al. DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system. Leukemia (2026). PubMed
Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013). PubMed
Piazza R, Magistroni V, Redaelli S, et al. SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Commun (2018). PubMed
Makishima H, Yoshida K, Nguyen N, 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
Makishima H, Yoshizato T, Yoshida K, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017). PubMed
Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022). DOI

[1] Polprasert C, Schulze I, Sekeres MA, Makishima H, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell (2015). PubMed

[2] Makishima H, Saiki R, Nannya Y, et al. Germ line DDX41 mutations define a unique subtype of myeloid neoplasms. Blood (2023). PubMed

[3] Gurnari C, Makishima H, Durmaz A, et al. DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system. Leukemia (2026). PubMed

[4] Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013). PubMed

[5] Piazza R, Magistroni V, Redaelli S, et al. SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Commun (2018). PubMed

[6] Makishima H, Yoshida K, Nguyen N, et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013). PubMed

[7] AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017). DOI

[8] Makishima H, Yoshizato T, Yoshida K, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet (2017). PubMed

[9] Bernard E, Tuechler H, Greenberg PL, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022). DOI