Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes

Abstract

Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventytwo (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia -11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

How I diagnose and treat chronic myelomonocytic leukemia

“…Recently, a 700kb germline duplication localized to 14.q32.2, resulting in overexpression of ATG2B and GSKIP genes has been described and has been associated with familial MPN and CMML 48 . Based on family histories, age of onset and the heterozygous nature of variant allele fractions, I routinely assess germline DNA from extracted hair follicles/skin fibroblasts to assess for germline predisposition syndromes 49 .…”

“… 48 Based on family histories, age of onset and the heterozygous nature of variant allele fractions, I routinely assess germline DNA from extracted hair follicles/skin fibroblasts to assess for germline predisposition syndromes. 49 …”

Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases

“…A clinically important feature of ANKRD26 -RT reported in the literature is the increased risk of developing hematological malignancy. AML and MDS are the most commonly described, though there are some reports of lymphoid malignancies and a single case report of a patient with a 5ʹUTR mutation developing multiple myeloma [ 6 , 10–12 , 16 , 20 ]. An extended case series of 118 subjects with confirmed or highly probable ANKRD26 -RT revealed an 8% incidence of myeloid malignancy (AML, MDS, and chronic myeloid leukemia (CML)) [ 10 ].…”

“…Some ITs are associated with extra-hematological manifestations such as sensorineural deafness ( MYH9 -related disease, DIAPH1 -related disease) or myopathy (Storkmorken syndrome) whilst others have a predisposition to hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS) [ 1–4 ]. At least 40 genes and their mutations have been implicated in the development of inherited thrombocytopenia [ 3 , 5 , 6 ]. Definitive identification of the genetic nature of thrombocytopenia can be important as some forms differ in disease history and prognosis.…”

Observation and treatment in DDX41-mutated acute myeloid leukemia and myelodysplastic syndrome

“…Additionally, allogeneic hematopoietic cell transplantation (HCT), the only potentially curative option, has been linked to higher non-relapse mortality and therefore potentially to consider delayed HCT at disease progression or relapse [ 4 , 6 ]. Some DDX41 mutations can potentially be of germline origin and such work-up is warranted in these cases [ 7 ]. mDDX41 MDS/AML cases tend to have indolent course, slow progression and higher hemoglobin and platelets indices [ 8 ].…”