Familial Myeloproliferative Disorders

Identity

Other names	Familial myeloproliferative neoplasms
	Hereditary erythrocytosis
	Hereditary thrombocytosis
Atlas_Id	10180
Genes implicated in	TERT  GSKIP  ATG2B  RBBP6  BML  BRCA2  BRIP1  CEBPA  ELANE  FANCA  FANCB  FANCC  FANCD2  FANCE  FANCF  FANCG  FANCI  FANCL  FANCM  HAX1  PALB2  RAD51C  RUNX1  SLX4  WAS
Note	Myeloproliferative neoplasms (MPN) are clonal and chronic hematological malignancies caused by genetic defects that result in overproduction of one or several myeloid lineages (erythroïd, megakaryocytic and granulocytic lineages). The classic MPN or Ph-chromosome-negative MPN include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Familial MPN are estimated to 2 to 10% according to studies. They are divided in two overlapping entities: - True MPN disorders with germline predisposition that are familial clustering of MPN with autosomal dominant inheritance and incomplete penetrance. These familial cases are indistinguishable from the sporadic cases of MPN in terms of clinical features and acquired genetic abnormalities. - Hereditary MPN-like disorders with clinical symptoms of MPN but affecting a single lineage involvement. They include hereditary thrombocytosis ( THPO, MPL, JAK2 genes), hereditary erythrocytosis ( EPOR, VHL, EGLN1 and EPAS1 genes) and hereditary neutrophilia ( gene). These hereditary disorders are non-malignant diseases and have distinct features: polyclonal hematopoiesis, absence of disease progression and autosomal dominant inheritance with complete penetrance.
Inheritance	Most of familial MPN are compatible with an autosomal dominant with incomplete penetrance. However, an autosomal recessive pattern has been suggested by some authors and could not be excluded.

Clinics

Phenotype and clinics	Familial MPN include the three classic MPN or Ph-chromosome-negative MPN: PV, ET, and PMF. Patients with familial MPN have the same clinical presentation at diagnosis as patients with sporadic MPN. They develop the same type of complications (thrombosis and hemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis, and acute myeloid leukemia). The distribution of MPN phenotypes within MPN families is homogeneous in half of cases (all affected family cases have the same MPN).
Neoplastic risk	RISK increased of transformation to acute myeloid leukemia (AML)
Treatment	The recommendations are those used for sporadic MPNS. In low-risk patients, phlebotomy in PV patients and low-dose aspirin in ET patients are recommended. In the presence of risk factors for thrombosis, hydroxyurea is used as first-line treatment and busulfan or interferon-α as second-line. Novel therapies based on JAK2 inhibitors have been developed and up to date, are restricted to patients with myelofibrosis.
Evolution	The main cause of death is the evolution to myelofibrosis and AML. In familial cases, the incidence annual rate of AML has been estimated to 1.25% patients/year for PV and 0.68% patients/year for ET.
Prognosis	Familial PV: 83% of overall survival at 10 years; Familial ET: 84% to 100% of overall survival at 10 years; Familial PMF: 30% of overall survival at 10 years.

Cytogenetics

Cytogenetics of cancer

Chromosomal aberrations observed in familial MPN are similar to those reported in sporadic cases. About two-third of MPN harbor at least one chromosomal aberration. Some of them are more specifically acquired with disease progression to secondary myelofibrosis such as uniparental disomy (UPD) of 9p, gain of 1q whereas others are more frequently associated with post-MPN acute myeloid leukemia such as gain of 1q, deletions of 7q, 5q, 6p, 7p, 3q and UPD of 19q and 22q.

Other findings

Note

MPNs are driven by at least one somatic acquired mutation (V617F in JAK2 or mutations in MPL and CALR for ET and PMF) and mutations in epigenetic regulators such as TET2, IDH1, IDH2 and . Familial MPNs harbor the same acquired somatic profile as sporadic MPN cases. Several predisposing single-nucleotide polymorphism (SNP) such as the JAK2 haplotype 46/1 (also named GGCC) in JAK2, SNP rs2736100 in TERT, SNP rs2201862 in MECOM and SNP rs9376092 in HBS1L / MYB have been shown to play a role in the development of MPN in the general population by favoring the acquisition of driver mutations. However, except TERT (detailed below, none of them explain the familial clustering of MPN.

Genes involved and Proteins

Gene Name	RBBP6
Location	16p12-p11.2

DNA/RNA
Transcription	NM_006910.4 encodes the longest transcript.

Protein
Description	Protein of 1792 amino acids.
Function	Possible link to P53 function.

Mutations
Germinal	All mutations located in the putative p53-binding region.

Gene Name	ATG2B (Autophagy-related protein 2 homolog B)
Location	14q32.2
Note	Cooperates with GSKIP, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).

DNA/RNA
Transcription	Unique transcript NM_018036.

Protein
Description	Protein of 2078 amino acids.
Expression	Expressed in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.
Function	Overexpression of ATG2B enhances hematopoietic progenitor differentiation, particularly in megacaryocytes and cooperates with classical driver mutations.

Mutations
Note	Founder defect in families originated from West-Indies.
Germinal	Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).
Somatic	Associated with classical driver mutations such as V617F in JAK2, W515L in MPL and 1099_1050del52 in CALR and with an increased frequency of mutations in TET2, IDH1 and IDH2.

Gene Name	GSKIP (GSK3-beta interaction protein)
Alias	C14orf129
Location	14q32.2
Note	Cooperates with ATG2B, also located in 14q32.2 and included in the 700 kb duplication NC_000014.9:g.95696766_96390792dup (on Assembly GRCh38).

DNA/RNA
Transcription	NM_001271904 encodes the longest transcript; 3 other transcripts encode the same protein with differences in the 5'UTR.

Protein
Description	Protein of 139 amino acids.
Expression	in CD34+ hematopoietic progenitors and during erythroïd and megakaryocyte differentiation.
Function	Overexpression of GSKIP enhances hematopoietic progenitor differentiation, particularly of megacaryocytes and cooperates with classical driver mutations.

Mutations
Note	Founder defect in families originated from West-Indies.
Germinal	Head-to-tail 700 kb tandem duplication (g.95696766_96390792dup).
Somatic	Associated with classical driver mutations such as V617F in JAK2, W515L in MPL and 1099_1050del52 in CALR and with an increased frequency of mutations in TET2, IDH1 and IDH2.

Gene Name	TERT (telomerase reverse transcriptase)
Location	5p15.33

DNA/RNA
Transcription	NM_198253.2 encodes the longest isoform (1); a shorter isoform lacking an alternate in-frame exon in the middle portion of the coding exon is also reported.

Protein
Description	Protein of 1132 amino acids.
Expression	Blood cells.
Function	Telomerase activity, essential for maintaining telomere length.

Mutations
Germinal	Allele C of SNP rs2736100, located in the second intron of the TERT gene, is associated with an increased risk for MPN (PV, ET and PMF).

To be noted

Germline duplication of ATG2B and GSKIP predispose with a high penetrance (above 80%) to several myeloid malignancies, particularly essential thrombocythemia frequently progressing to AML. RBBP6 germline gain-of-function mutations mostly associated with primary myelofibrosis, observed in 5% of the familial and 0.6% of the sporadic MPN cases. TERT rs2736100_C risk allele is significantly associated with familial MPN, whatever the subtype (PV, ET and PMF

Bibliography

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Citation

This paper should be referenced as such :

Bellanné-Chantelot C, Plo I

Familial Myeloproliferative Disorders;

Atlas Genet Cytogenet Oncol Haematol. in press

On line version : http://AtlasGeneticsOncology.org/Tumors/FamMyeloproliferID10180.html

External links

OMIM	187950
OMIM	254450
OMIM	601626
Other database	ClinVar : SCV000224007-4010

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