Haematological malignancies in relatives of patients affected with myeloproliferative neoplasms

Abstract In a cohort of 3131 patients with myeloproliferative neoplasms (MPNs), we identified 200 patients (6.4%) who reported a second case of haematological malignancies (HM) in first‐ or second‐degree relatives. The occurrence of a second HM in the family was not influenced by MPN subtype, sex or driver mutation, while it was associated with age at MPN diagnosis: 8.5% of patients diagnosed with MPN younger than 45 years had a second relative affected with HM compared to 5.5% of those diagnosed at the age of 45 years or older (p = 0.003), thus suggesting a genetic predisposition to HM with early onset.


INTRODUCTION
Myeloproliferative neoplasms (MPNs) are a heterogenous group of clonal diseases, characterized by an increased production of differentiated haematopoietic cells, that occur mostly in a sporadic way [1]; however, a non-trivial proportion of cases (7.6%) are, indeed, familial [2,3]. In this regard, patients' relatives have a five to seven fold higher risk of developing MPN compared to the general population [4]. This notion has been recently confirmed and extended to other subtypes of myeloid neoplasms, thanks to two large, population-based studies that focused on familial aggregation of haematological neoplasms [5,6]. Even though first-degree relatives had the strongest relative risk for the same disease showed by the index case, a more general, increased risk of all myeloid malignancies emerged, that correlated with the number of affected relatives and, especially for MPN, with younger age of the index case [5]. Moreover, there was evidence for pleiotropic associations among lymphoid and myeloid malignancies [4], supporting the hypothesis of a shared aetiology [7], either inherited [8] or environmental [9,10]. In the present study, we aimed at estimating risk of haematological malignancies (HMs) among relatives of MPN patients and performed whole exome sequencing (WES) on four patients from two representative families.

Patients
We interrogated our database of MPN patients, followed at our institution from 1970 to 2020, to identify patients that reported at least a sec-

METHODS
DNA for driver mutation analysis was available in 2392 of 3131 patients. JAK2 V617F mutation, CALR exon 9 mutations and MPL exon 10 mutations were assessed as previously described [11].
In two representative families with several cases of HM (family #126 and family #127 reported in Figure 1A) (Table S2) and 145 in family #127 (Table S3). None of these variants are known to be responsible for MPN phenotype. We also explored the structural variant (SV) calls that are invariably detected in both affected cases of each family and found 7 SV in family #126 (Table S4) and 7 SV in family #127 (Table S5). However, these abnormalities are unlikely pathogenetic because AHNAK2 substitutions are located in a simple repeat region, and CLCN7 deletion is located within an intron and is unlikely to affect the coding region coordinates. Also, when considering the shared protein family the corresponding proteins belong to, the affected genes are unlikely to have a role in the pathogenesis of MPN disease.

DISCUSSION
Our findings, in a well-annotated, large, monocentric cohort of MPN patients, confirm a high familial risk of HM, with a striking prevalence for myeloid neoplasms. It has been previously recognized that MPN patients have an increased risk of developing second primary malignancies [14,15]. Our observations are in line with two previous papers that identified familial associations of cancer diseases that extended across different hematopoietic cell lineages [6,7].
Consistent with the notion that patients diagnosed with cancer at a younger age are more likely to have a genetic predisposition [7], frequency of HM among patients' relatives was linked to age at MPN diagnosis of the index case.
We acknowledge that our study has intrinsic limitations due to the retrospective design and due to a potential risk of missing data or under-reported diagnoses because family members were not further followed after death of the proband. As a consequence, we could speculate that we have preferentially collected information on families with cancer diagnosed in older individuals (i.e., grandparents and/or parents, when a son is the index MPN case) compared to families with two affected siblings.
In conclusion, our findings support the hypothesis of a significant familial aggregation of HM and underline the importance of pursuing deep-sequencing approaches in accurately selected families. Unfortunately, in our representative families we did not find the pathogenetic event but we hope that an improved knowledge would be clinically relevant, since it could improve both management and counselling of patients with haematological neoplasms and their relatives.