Shared Genomic Alterations in Patients with Co-Existing Myeloproliferative Neoplasms and Angioimmunoblastic T-Cell Lymphoma
Authors: Holst Johanne Marie , Pedersen Martin Bjerregaard , Hansen Marcus C , Plesner Trine Lindhardt , Frederiksen Henrik , Møller Michael , Hamilton-Dutoit Stephen , Noergaard Peter , Mortensen Bo Kok , Fiore Danilo , Wang Chao , Zhang Weiwei , Tam Wayne , Ludvigsen Maja , Chan Wing C. , Inghirami Giorgio , d'Amore Francesco 
Published: November 2019

Background: Myeloproliferative neoplasia (MPN) and angioimmunoblastic T-cell lymphoma (AITL) are two distinct hematologic cancers. However, we have shown that patients with both malignancies probably occur with frequencies higher than expected in the background population (1,2). AITL tumors show a high frequency (30-70%) of mutations in RHOA and epigenetic modifier genes such as DNMT3A, TET2 and IDH2. The latter genomic alterations are similar to those found in myeloid diseases such as MPN. This observation has raised questions on whether the two hematologic malignancies may share genomic aberrations (e.g. at progenitor level) suggesting a possible pathogenetic relationship between these diseases.
Aim: To further investigate these questions, we explored the mutational landscape in MPN and AITL tumors occurring in the same host.
Methods: From a Danish cohort of 97 patients with co-existing MPN and lymphoma identified through the Danish Lymphoma and Pathology Registries and immunohistochemically validated by tertiary center hematopathologists, five patients with MPN and concurrent and/or subsequent AITL were included. Paired DNA samples obtained from lymph node biopsies (AITL component), bone marrow aspirates (MPN component) and saliva specimens (normal reference DNA) were analyzed by whole exome sequencing. A minimum variant allele frequency threshold of 10% was applied. However, mutations in epigenetic modifier genes, RHOA and JAK2, were also included, if found at slightly lower frequencies.
Results: Figure 1 shows an overview of the identified mutations. At a VAF% cut-off value of 10 and a median coverage of 30, mutations shared between the MPN and AITL specimens were found within the DNMT3A, TET2, and IDH2 genes. Mutations in the JAK2 gene were identified in all MPN and in some of the AITL samples. NOTCH2 mutations were frequent and some were shared between the MPN and AITL samples. Two patients with essential thrombocytosis and AITL had the same NOTCH2 (C19W) and NCOR1 (K178N) mutation. Most of the identified genomic alterations were inactivating missense mutations.
Conclusion: Co-existence of MPN and AITL occurs and may not be a random event. We studied tumor tissues from patients diagnosed with both diseases, and identified recurrent shared and non-shared mutations in samples from both types of cancers. These mutations may contribute to the development of the two malignancies in the same host, partly through common steps at precursor level (e.g. DNMT3A) and partly more downstream at a more lineage-specific level (e.g. IDH2). The functional role of the observed NOTCH2 and NCOR1 mutations is currently under investigation.
Holst J et al. Blood 2017, 130 (S1): 1525 Frederiksen H et al. Blood 2011;118(25):6515-6520

Disclosures
Tam: Takeda: Consultancy; Paragon Genomics: Consultancy.