ABSTRACT
Rhabdomyosarcoma (RMS) is a highly aggressive pediatric cancer known for
its therapeutic challenges, particularly when it becomes metastatic or
recurrent. Traditional treatment approaches have shown limited success,
prompting a growing interest in targeted therapies. The emergence of
next-generation sequencing (NGS) has revolutionized our ability to
identify actionable mutations in RMS, offering the promise of
personalized treatments and improved patient outcomes. A recent case
involving a 3-year-old child diagnosed with embryonal RMS highlighted
the potential of next-generation sequencing (NGS) in clinical practice.
Despite receiving initial chemotherapy, the patient’s tumor showed
progressive growth. What made this case particularly intriguing was the
discovery of co-occurring somatic mutations in the RAS/MAPK pathway,
specifically in BRAF and HRAS genes, which are traditionally believed to
be mutually exclusive.
Notably, the BRAF mutation identified in this case, N581I, is a
non-classical (Class III) hotspot mutation that had not been previously
reported in embryonal RMS. This novel finding underscores the critical
importance of comprehensive genetic profiling in pediatric cancers and
suggests the existence of potential therapeutic avenues that target BRAF
alterations.
In conclusion, the integration of NGS technologies in clinical practice
holds great promise for identifying previously unrecognized mutations in
pediatric cancers like RMS. These findings have the potential to open up
new treatment options and improve outcomes for young patients facing
this aggressive disease.
INTRODUCTION
Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer originating
from embryonic mesenchymal tissue1, and remains a
formidable therapeutic challenge due to its ability to manifest in
diverse anatomical sites2. Despite conventional
treatments, including chemotherapy, surgery, and radiotherapy, the
overall survival rate for metastatic and recurrent RMS patients remains
low. This bleak scenario has propelled interest in exploring targeted
therapies, particularly in high-risk patients and those with aggressive
and relapsed disease. Recent advancements in next-generation sequencing
(NGS) and computational analyses have revolutionized the study of
somatic mutations across various cancer types, shedding light on novel
opportunities for precision medicine in RMS and beyond.
Sidra Medicine, the single pediatric cancer care institution in Qatar,
has initiated the Sidra Pediatric Precision Oncology Program, aiming to
provide research-grade tumor sequencing for pediatric solid tumor
patients. This initiative offers an unparalleled avenue for molecular
characterization that guides both diagnosis and treatment.
In this context, we present a case report of a young patient with
embryonal RMS, treated at Sidra Medicine. In our patient, we identified
the co-occurrence of two actionable mutations in the HRAS and BRAF genes
part of the RAS/MAPK pathway. These mutations are traditionally observed
as mutually exclusive, and their combination has never been reported (to
our knowledge) in embryonal RMS.
METHODS
Informed written consent was obtained from the patient for participation
in the study (SDR SDR200074 / IRB 1509000). The institutional review
board approved this study (conducted at Sidra Medicine). At
presentation, his tumor was diagnosed with the standard
histopathological examination at the referring center. At the time of
progression, further analysis was carried out on the tumor DNA extracted
from the FFPE specimen by next-generation sequencing (NGS) technique.