Potential Sarcoma Susceptibility Genes Identified

Pathogenic variants were found in a substantial portion of 41 patients living with soft tissue sarcoma (STS), with experts highlighting 2 genes as playing vital roles in disease development: MYO5B and MYO3A.

Findings of the retrospective analysis were published in Acta Oncologica.¹

Pathogenic variants are considered risk factors for development of diseases/disorders. Their presence may not always result in an adverse outcome, but there is a greater likelihood of that occurring; particularly when these variants, also known as mutations, are inherited.²

Among the overall patient population, the most common STS subtype was rhabdomyosarcoma (24 diagnoses), followed by synovial sarcomas (9 diagnoses), Ewing sarcoma (2 cases), and unclassified (6 cases). The patients ranged in age from 0 months to 22 years, comprising pediatric and young adult patient populations; their mean (median) age at diagnosis was 10.4 (11.0) years, and they received care between 1981 and 2019 at Haukeland University Hospital in Norway.

When drilling down to sarcoma subtypes in this analysis, the authors found that patients with rhabdomyosarcoma had 6 of the 7 identified variants while the patients with synovial sarcoma or Ewing sarcoma had none. | Image Credit: Atro-stock.adobe.com

Seventeen percent of the 41 cases—22 female patients and 24 male patients overall, but only 41 patients had adequate tissue for sampling—exhibited pathogenic variants or likely pathogenic variants, the authors stated. The genes these were found in were TP53, MUTYH, FANCC, DICER1, FANCA, MYO3A, and MYO5B. For many sarcomas, the authors emphasized, there are a lack of data on how germline alterations contribute to these cancers in pediatric patients. They used both normal tissue samples and tumor tissue samples for their investigation, and analyzed the DNA from these samples through sequencing of a 360 cancer gene panel.

The most common tumor location was the extremities (28%), followed by the trunk (25%), head and neck area (22%), genitourinary tract (11%), pelvic or abdominal area (5.6% each), and gynecologic area (2.8%).

Of the genes identified, TP53, MUTYH, FANCC, DICER1, and FANCA are known cancer predisposition genes, while MYO3A and MYO5B have been linked to both cancer and deafness and microvillus inclusion disease, respectively, the authors noted.^3,4 The authors also detected germline variants in MYO3A and MYO5B.

TP53, DICER1, FANCC, and FANCA have, in particular, been linked to a greater risk of rhabdomyosarcoma, with primary tumor types being embryonal rhabdomyosarcoma (TP53, DICER1), rhabdomyofibrosarcoma (FANCC), and osteosarcoma (FANCA). Patients, too, who had variants of MYO3A and MYO5B also had rhabdomyosarcoma.

“These genes have not previously been shown to be associated with elevated risk of either RMSs, Ewing sarcoma, or soft tissue sarcomas in general,” the authors wrote.

Overall, when drilling down to sarcoma subtypes, patients with rhabdomyosarcoma had 6 of these 7 identified variants while the patients diagnosed with synovial sarcoma or Ewing sarcoma had none. Results were similar when considering gender, with 4 of 7 and 3 of 7 found in the male patients and female patients, respectively.

Family history was also evaluated. Among the 3 patients who had a family history of cancer, these patients were shown in the present study to have variants in TP53, FANCA, and DICER.

Last, the study investigators examined variants of unknown significance, with the goal of findings previously unknown triggers of early-onset STS. With this analysis, they found 28 variants of unknown significance, and these included NOTCH2, ABL2, IDH1, EGFR, PAX9, and JAK3. The authors noted that few of these were recurring, with the entire patient population of their study harboring an average 0.7 variants of unknown significance, but that these variants affected “a broader repertoire”. There was an age gap in STS diagnosis between those with pathogenic variants (7 years) and variants of unknown significance (13 years), but this result was deemed not statistically significant.

“Although these observations should be seen as anecdotal observations,” the authors concluded, “we believe they warrant further investigations into the potential link between genetic alterations in developmental defect syndromes and sarcomas.”

References

1. Yndestad S, Haugland HK, Goplen D, Wojcik D, Knappskog S, Lønning PE. Germline variants in patients diagnosed with pediatric soft tissue sarcoma. Acta Oncol. 2024:63:586-591. doi:10.2340/1651-226X.2024.40730

2. Pathogenic variant. National Cancer Institute. Accessed August 8, 2024. https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/pathogenic-variant

3. Walsh T, Walsh V, Vreugde S, et al. From flies’ eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A. 2002;99(11):7518-7523. doi:10.1073/pnas.102091699

4. Muller T, Hess MW, Schiefermeier N, et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008;40(10):1163-1165. doi:10.1038/ng.225