Myeloproliferative neoplasms and somatic mosaicism in the 23andMe participant community. D. A. Hinds1, K. E. Barnholt1, J. L. Zehnder2, A. K. Kiefer1, C. B. Do1, N. Eriksson1, J. L. Mountain1, U. Francke1, J. Y. Tung1, R. L. Levine3, R. A. Mesa4, J. R. Gotlib5 1) 23andMe, Inc., Mountain View, CA; 2) Department of Pathology and Department of Medicine/Hematology, Stanford University School of Medicine, Stanford, CA; 3) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; 4) Division of Hematology & Medical Oncology, Mayo Clinic, Scottsdale, AZ; 5) Department of Medicine/Hematology, Stanford University School of Medicine, Stanford, CA.

   Background: Myeloproliferative neoplasms (MPNs) are disorders that result in unregulated overproduction of one or more myeloid blood cell types by the bone marrow. Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the three classic MPNs. A somatic JAK2 mutation, V617F, is present in 95% of PV and 50-60% of ET and PMF patients. Past work has identified germline variation in JAK2 associated with risk of developing a V617F-positive MPN. Methods: We have recruited a web-based participatory cohort of patients with MPNs to better understand the genetic basis of these conditions. We have enrolled and collected saliva samples from more than 600 participants, including the following self-reported diagnoses: systemic mastocytosis (n=130), ET (n=115), PV (n=107), PMF (n=50), chronic myeloid leukemia (n=70), and 79 with overlapping diagnoses. Participants have been genotyped using a derivative of the Illumina OmniExpress with additional custom content, including probes for V617F. Results: We can detect V617F with high specificity and sensitivity, indicating that a portion of the DNA we extract is of myeloid origin. We also observe large-scale chromosomal alterations previously seen in MPNs, including uniparental disomy of chromosome 9p. We detect V617F and larger chromosomal alterations at low frequency in the broader 23andMe community. These variants have been associated with increased cancer risk and we are developing strategies for communicating this information and conducting follow-up studies with our participants. In genome-wide association analyses, we replicate the known association between V617F and germline variation in JAK2 (rs12340895: odds ratio=3.2, P=3.2e-41). We also detect a novel association between MPNsET, PV, and PMFand rs2853677 (odds ratio=1.5, P=8.7e-08) in telomerase reverse transcriptase (TERT). Variation in TERT has previously been associated with multiple non-hematological cancers, and our lead SNP is in linkage disequilibrium with the previously associated TERT variants. The high-risk allele of rs2853677 is also predictive of V617F status among 23andMe participants who were not recruited into the MPN community (odds ratio=1.6, P=0.0014). Conclusion: We have identified a germline variant in TERT which is a novel predisposition allele for MPNs. These results demonstrate the potential for web-based recruitment methods to contribute to genetic research for uncommon diseases.

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