Pediatric Soft Tissue Sarcoma in Limb-Girdle Muscular Dystrophy: Molecular Findings and Clinical Implications

Abstract

BACKGROUND Limb-girdle muscular dystrophy recessive 1 (LGMDR1) is an autosomal recessive degenerative muscle disorder characterized by progressive muscular weakness caused by pathogenic variants in the CAPN3 gene. Desmoplastic small round cell tumors (DSRCT) are ultra-rare and aggressive soft tissue sarcomas usually in the abdominal cavity, molecularly characterized by the presence of a EWSR1::WT1 fusion transcript. Mouse models of muscular dystrophy, including LGMDR1, present an increased risk of soft tissue sarcomas. However, the DSRCT risk and general cancer risk in patients with LGMD is unknown. Here, we delineate the clinical, molecular, and genetic findings of a patient with LGMDR1 who developed a DSRCT. CASE REPORT The patient was a boy who was diagnosed at the age of 9 years with LGMDR1, caused by the biallelic pathogenic variants NP_000061.1:p.(Arg448Cys) and NP_000061.1:p.(Thr184ArgfsTer36) in CAPN3. At 17 years of age, a pathologic soft tissue mass was found in the right pelvis. Immunostaining was positive for Desmin and negative for Myogenin and MyoD1, and RNA sequencing showed a EWSR1::WT1 fusion transcript, confirming the diagnosis of DSRCT. The patient relapsed after 1 year and, following a second relapse, he was started on palliative treatment. No germline variants in childhood cancer predisposition genes were detected by whole genome sequencing. CONCLUSIONS We describe a patient with LGMDR1 who developed a DSRCT. Since associations between LGMD and pediatric cancer are hitherto unknown, further studies are warranted, as little information is currently published about the pediatric cancer risk in this patient group.

Figure 1.

Diagnostic findings in the primary and relapse tumors. (A, B) Histology of core biopsies in the primary tumor. (A) Hematoxylin and eosin (HE) staining showing malignant small blue round cell tumor with hyperchromatic, immature, rounded cells with scant cytoplasm growing in a partly solid and partly trabecular pattern in a desmoplastic stroma. (B) Positive perinuclear cytoplasmic and focally dotlike Desmin staining. (C, D) Histology of open biopsies in the second relapse, scalp tumor. (C) HE staining showing a malignant small blue round cell tumor with oval to rounded cells with hyperchromatic nuclei and scant cytoplasm in a desmoplastic stroma. (D) Desmin immunostaining with perinuclear cytoplasmic pattern. (E) Visualization of RNA sequencing results from the soft tissue sarcoma, showing the EWSR1::WT1 fusion transcript. The upper part of the figure displays the fusion partners with their chromosomal localization (GRCh38) and orientation, while the lower part visualizes the predicted fusion transcript and the retained exons. All histology figures are presented at a magnification of 40×.

Figure 2.

Genomic profiles of the primary and relapse tumors. Copy-number profiles, ploidy, and tumor cell ratio from whole genome sequencing of tumor material generated by ASCAT [43]. For each figure, the upper panel shows the allele-specific copy number across the genome (copy number on y axis vs genomic location on the x axis). The allele with the lowest copy number is shown in green, while that with highest copy number, in red. For illustrative purposes, both lines are slightly shifted (red, down; green, up) such that they do not overlap. Only germline heterozygous probes are shown. In the middle and lower panels, the normalized log transform of read depth (LogR) and B-allele frequencies (BAF) values overlaid with segmented LogR and BAF across the genome are shown, respectively, representing the relative presence of each allele. (A) Near triploid desmoplastic small round-cell tumor showing multiple numerical and segmental chromosomal aberrations, including 1q gain (5 copies) and loss of heterozygosity in chromosomes 6 and 16. (B) The relapsed scalp tumor was also near triploid. Multiple aberrations were shared with the primary tumor, while new rearrangements emerged in specific chromosomal regions, such as 1p loss, 4q gain, loss of heterozygosity in chromosomes 11 and 13, and 15q rearrangements, which may suggest the involvement of genomic instability in the evolution of the tumor.