Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms

SIMPLE SUMMARY: Familial 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. ABSTRACT: 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.