Prevalence of cytopenia(s) and somatic variants in patients with DDX41 mutant germline predisposition syndrome

Abstract

Germline variants in DDX41 (DDX41^MT-germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41^MT-GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2-93.4). Ninety-two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41^MT-GPS cohort.

Keywords: AML; CCUS; CHIP; MDS; germline DDX41; germline predisposition syndromes.

FIGURE 1

(A) Lolliplot depicting the location and frequency of germline DDX41 variants (top) and somatic variants (bottom). (B) Number of patients with DDX41 ^MT‐GPS pathogenic versus VUS based on type of variant. (C) Frequencies of phenotypes encountered. (D) Distribution of patients among Group 1, Group 2 and Group 3. (E) Number of patients per germline variant within each group. The top 32 variants are shown, variants only present 1x in the cohort are not shown. Pathogenic variants are labelled in red. GPS, germline predisposition syndrome; VUS, variants of unknown significance.

FIGURE 2

(A) Numbers of patients with DDX41 ^MT‐GPS stratified by molecular and clinical characteristics. (B) Oncoplot displaying germline variant, group, haematological diagnosis and concomitant somatic variant for each patient with somatic variants detected. Patients without identified variants are not shown. GPS, germline predisposition syndrome. GPS, germline predisposition syndrome.

FIGURE 3

(A) Differences in the top eight pathogenic somatic variants detected among diagnoses. (B) Violin plot of VAFs of the entire cohort. (C) Progression‐free survival (PFS, Kaplan–Meier) for patients with CH/CCUS. On univariate and multivariate analyses, somatic DDX41 did not impact PFS. (D) Overall survival (OS, Kaplan–Meier) for AML patients. On univariate and multivariate analyses, TP53 negatively impacted outcomes while somatic DDX41 did not. (E) IPSS‐R and (F) IPSS‐M scores for patients in the cohort with MDS. (G) PFS (Kaplan–Meier) for MDS patients. On univariate and multivariate analyses, somatic DDX41 did not impact PFS. (H) OS (Kaplan–Meier) for MDS patients. On univariate and multivariate analyses, somatic DDX41 did not impact OS. *p < 0.05, **p < 0.01, ***p < 0.001. AML, acute myeloid leukaemia; CCUS, clonal cytopenia of undetermined significance; CH, clonal haematopoiesis; MDS, myelodysplastic syndrome; VAF, variant allele fraction.