Identification of novel potential predisposing variants in familial
acute myeloid leukemia
Abstract
Myeloid neoplasms, including acute myeloid leukemia, have been
traditionally among the less investigated cancer types concerning
germline predisposition. Indeed, myeloid neoplasms with germline
predisposition are challenging to identify because often display similar
clinical and morphological characteristics of sporadic cases and have
similar age at diagnosis. However, a misidentification of familiarity in
myeloid neoplasms have a critical impact on clinical management both for
the carriers and their relatives. We performed a thorough genomic
analysis using a large custom gene panel, the Myelo-Panel, targeted on
cancer predisposing genes. In particular, we assessed both germline and
somatic variants in 4 families, each with two siblings, who developed
hematological neoplasms: 7 acute myeloid leukemia and 1
Philadelphia-positive chronic myeloid leukemia. In each family, we
identified at least one novel potentially predisposing variant,
affecting also genes not included in the current European LeukemiaNet
guidelines for AML management. Moreover, we suggest reclassification of
2 germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in
CEPBA and VUS p.K392Afs*66 in DDX41. Our data underline
how familiar predisposition to hematological neoplasms is currently
underestimated and call for revision of clinical practices that should
include thorough reconstruction of family history and genetic testing
with gene panels targeted for cancer predisposing genes.