Comprehensive genomic sequencing is becoming a critical component in the assessment of
hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of
tumor:normal pairs. In contrast to solid
tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using
cell free DNA (
cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610
tumor:nail pairs comprehensively sequenced by MSK-IMPACT-
heme. Overall, we find nail
cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail
DNA may have
tumor DNA contamination, reflecting unique attributes of the
hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid
neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative
neoplasms with marked
myelofibrosis. When identified in patients with lymphoid and
plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid
neoplasm. For nails collected after allogeneic
stem-cell transplantation, donor
DNA was identified in 22% (11/50). In this cohort, an association with recent history of
graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.