The myogenic differentiation 1 gene (MYOD1) p.L122R somatic mutation was
first discovered in a subset of clinically aggressive embryonal
rhabdomyosarcomas and has since been described in both pediatric and adult
spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about
the clinical, molecular, and histopathological features of these tumors in
children. In order to further characterize the genomic and clinical
features of pediatric MYOD1-mutant sarcomas, we evaluated a cohort of
soft-tissue sarcoma patients treated at Texas Children’s Hospital. Tumor
DNA was subjected to next-generation panel sequencing and/or Sanger
sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was
identified in six tumors, with a variant allele fraction greater than 0.8
in three cases, suggestive of loss of heterozygosity. One sclerosing
rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a
MYOD1 copy number gain, also with evidence of loss of heterozygosity.
Cancer gene panel sequencing revealed potentially targetable alterations in
six of seven (86%) patients with MYOD1 alterations, including four patients
with an alteration in the PI3K-AKT pathway: two hotspot PIK3CA mutations
and deletions in PTEN and TSC2. On histopathologic review, MYOD1-altered
tumors exhibited spindle and/or round cells and varying degrees of hyaline
sclerosis. At last follow-up, six patients had died of disease and the
seventh progressed early and was subsequently lost to follow-up. Both pre-
and post-therapy patient-derived xenograft models were generated from one
patient’s tumor. These models were confirmed to harbor the MYOD1 and PIK3CA
mutations seen in the primary tumor and were shown to be sensitive to
PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds
to recent reports describing the clinicopathologic and genomic features of
MYOD1-altered soft-tissue sarcomas in children, including dismal prognosis
and potential molecular targets for therapy. The novel preclinical models
developed will facilitate further biological and preclinical study of this
rare and aggressive tumor. © 2021 The Pathological Society of Great Britain
and Ireland. Published by John Wiley & Sons, Ltd.