-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

1763 Familial Predisposition in Myeloproliferative Neoplasms: An NGS-Driven Analysis

Program: Oral and Poster Abstracts
Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Adult, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Luca Di Marino1*, Francesco Ramundo2*, Tanja Malara, MD3*, Monica Rossi, MD4*, Roberto Maggi, MD5*, Federica Fosso6*, Silvia Betti7*, Elena Rossi, MD8*, Giuseppe Leone, Prof9, Simona Sica, MD, PhD10*, Valerio De Stefano, MD8* and Patrizia Chiusolo, MD, PhD11*

1Dipartimento di Scienze di Laboratorio ed Ematologiche-Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma, Italy
2Institute of Hematology, Catholic University School of Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Roma, Italy
3Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
4Dipartimento di Scienze di Laboratorio ed Ematologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
5Dipartimento di Scienze di Laboratorio ed Ematologiche-Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, AL, ITA
6Dipartimento di Scienze di Laboratorio ed Ematologiche-Fondazione Policlinico Universitario Agostino Gemelli-IRCCS, Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, ITA
7Ematologia Universita Cattolica Sacro Cuore, Roma, Italy
8Fondazione Policlinico Gemelli IRCCS, Section of Hematology, Catholic University, Rome, Roma, Italy
9Catholic University of Sacred Heart, Roma, RM, ITA
10Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
11UOC Ematologia e Trapianto Cellule Staminali Emopoietiche, Fondazione Policlinico Universitario A. Gemelli IRCCS Roma, Rome, Italy

Introduction

Myeloproliferative neoplasms (MPNs) are mostly considered neoplasms that arise in adulthood following the acquisition of somatic mutations; however, it is often possible to identify a tendency for clustering of these neoplasms within certain families. To date, except for hereditary forms due to the MPL mutation, no genes are known to be associated with a higher susceptibility to these neoplasms. This study aims to identify germline mutations linked to familial predisposition to MPNs.

Materials and Methods

This monocentric, biological, retrospective study enrolled patients with MPNs who were followed at our center over the past 10 years. A targeted Next Generation Sequencing (NGS) analysis was performed on peripheral blood samples, using a 70-genes panel. Genes are selected based on the available evidence for Hereditary cancer syndromes. Data interpretation was performed using BaseSpace Variant Interpreter and variants were classified into 5 categories based on ACMG guidelines: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Benign and likely benign variants were excluded from our analysis.

Results

We analyzed samples from 54 subjects (32 females, 22 males) affected by myeloid neoplasms (MNs), all of whom had at least one family member also affected by MNs. Twenty-nine subjects (53.7%) had a first-degree relative affected; 22 (40.7%) had a second-degree relative affected; and only 3 (5.6%) had a relative affected at the third degree or higher. Of the 54 subjects, 32 (59.3%) had a family member within the study, providing genomic data for 16 pairs of first-degree relatives.

The most frequent diagnosis was Essential Thrombocythemia (n=25, 49.3%), followed by Polycythemia Vera (20, 37.0%) and Myelofibrosis (5, 9.3%). One subject (1.8%) had unclassifiable MPN and another one (1.8%) had chronic myeloid leukemia (CML). Two (3.7%) subjects had acute myeloid leukemia (AML) and were included as both were siblings of subjects enrolled in the study and affected by MPNs.

JAKV617F was found to be the most common driver mutation (n=39, 72.2%), followed by CALR (n=4, 7.4%) and MPL (n=3, 5.6%). Five (9.3%) subjects were triple-negative, while BCR-ABL was identified in the subject with CML and in one of the subjects with AML, who had also the MPL mutation. The other AML patient had no mutations and in one (1.8%) case driver mutation was not available.

The most frequently mutated genes are ATM (n=8, 14.8%), CHEK2 (n=4, 7.4%), FANCD2 (n=3, 5.6%), ANKRD26 (n=3, 5.6%), APC (n=3, 5.6%), ATG2B (n=3, 5.6%), NF2 (n=2, 3.7%), RET (n=3, 5.6%), TSC2 (n=3, 5.6%), BMPR1A (n=2, 3.7%), PMS2 (n=2,3.7%), RTEL1 (n=4, 7.4%), MECOM (n=3, 5.6%), POLD1 (n=2, 3.7%), and POLE (n=4, 7.4%).

Considering only the 32 patients for whom analysis of both family members was available, the ATM mutation remained the most frequent, present in 6 (11.1%) subjects, with each of the 3 pairs presenting a specific mutation. The ATM mutations identified are Arg2506ThrfsTer3, Gly2508Arg, Arg2719Cys, Leu2492Arg, and Gly3029Asp (1 pathogenic, 1 likely pathogenic, and 3 variants of uncertain significance), all affecting the C-terminal region of the protein where the kinase domain and FAT and FATC portions are located, necessary for the protein's interaction with its ligands and its role in DNA repair.

Conclusions

Our data analysis highlighted the presence of a series of mutations in genes involved in DNA repair, transcription and telomere regulation. In particular, the most frequently mutated gene is ATM, whose germline mutations are known to be associated with the development of various tumors. Our preliminar findings align with recent work by Guijarro1, who identified a germline ATM mutation in 6.4% of subjects diagnosed with AML and MDS, although further data are necessary.

References

  1. Guijarro F, López-Guerra M, Morata J, Bataller A, Paz S, Cornet-Masana JM, Banús-Mulet A, Cuesta-Casanovas L, Carbó JM, Castaño-Díez S, Jiménez-Vicente C, Cortés-Bullich A, Triguero A, Martínez-Roca A, Esteban D, Gómez-Hernando M, Álamo Moreno JR, López-Oreja I, Garrote M, Risueño RM, Tonda R, Gut I, Colomer D, Díaz-Beya M, Esteve J. Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome. Blood Adv. 2023 Oct 10;7(19):5799-5811. doi: 10.1182/bloodadvances.2023009742. PMID: 37450374; PMCID: PMC10561046.

Disclosures: De Stefano: Novartis: Speakers Bureau; Leo Pharma: Speakers Bureau; Takeda: Speakers Bureau; Alexion: Research Funding; Sanofi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Alexion: Speakers Bureau; Abbvie: Speakers Bureau; Grifols: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Sobi: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH