Abstract
Simple SummaryFamilial clustering of myeloproliferative neoplasms (MPN) is well known, with a 5- to 7-fold increased risk of MPN among first-degree relatives of MPN patients. However, the genetic susceptibility of this disease remains poorly understood. Exome sequencing of a familial MPN pedigree followed by a case-control analysis identified germline variants in the HER2/ERBB2 gene that associate with the MPN phenotype. ERBB2/HER2 is a novel susceptibility locus which contributes to cancer risk in combination with additional risk alleles.Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.
Highlights
The myeloproliferative neoplasms (MPN) are usually sporadic diseases characterized by increased JAK/STAT pathway signaling due to a somatic driver mutation in either the JAK2, CALR, or MPL gene
In order to identify novel predisposition genes in MPN, we investigated a family with a highly penetrant, autosomal dominant familial cancer syndrome (Figure 1A, Table6So1f)1.1The proband was diagnosed with polycythemia vera (PV) at age 38, with a JAK2 p.V617F variant allele frequency (VAF) of 47%
We previously identified a rare ERBB3 germline variant that co-segregated with disease in a pedigree with familial erythroid myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), implicating this gene family in predisposition to blood cancers [30]
Summary
The myeloproliferative neoplasms (MPN) are usually sporadic diseases characterized by increased JAK/STAT pathway signaling due to a somatic driver mutation in either the JAK2, CALR, or MPL gene. Familial cases of MPN are well described; approximately 10% of MPN cases display familial clustering, and there is a 5- to 7-fold increased risk of developing an MPN among first-degree relatives of MPN patients [1,2,3]. Similar to other familial hematologic cancers, affected families tend to display an autosomal dominant inheritance pattern with incomplete penetrance. In contrast to other myeloid malignancies, investigation of large pedigrees with familial clustering of MPN has failed to identify high-risk predisposition genes. Germline variants in the gene RBBP6 were found to co-segregate with disease in three pedigrees with familial MPN, albeit with incomplete penetrance [4]. MPN was found to be part of the spectrum of hematologic malignancies in a large cohort with germline DDX41 variants [7]. In the majority of familial MPN cases, the genetic risk factors leading to development of malignancy are unknown
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