MLH1 – Rhabdomyosarcoma

Germline loss-of-function variants in MLH1 cause Lynch syndrome and predispose to colorectal and other neoplasms. A single unrelated individual has been reported with pleomorphic Rhabdomyosarcoma: a 19-year-old presented with metastatic, chemoresistant pleomorphic RMS and carried a heterozygous MLH1 c.1863_1864insT (p.Leu622SerfsTer10) frameshift variant with somatic loss of heterozygosity in the tumour ([PMID:30352869]). No familial segregation or additional probands have been described.

Tumour immunohistochemistry demonstrated complete loss of MLH1 and PMS2 nuclear expression and high PD-L1 positivity (60% of tumour cells), confirming mismatch repair deficiency and guiding successful anti-PD-1 therapy with a sustained complete response at one year ([PMID:30352869]). This observation highlights the diagnostic utility of MLH1 testing in rare adult sarcomas and the potential for immunotherapy in mismatch repair–deficient tumours. Key take-home: MLH1 loss can underlie chemoresistant pleomorphic RMS and inform precision oncology decisions.

References

• Journal of medical genetics • 2020 • Chemoresistant pleomorphic rhabdomyosarcoma: whole exome sequencing reveals underlying cancer predisposition and therapeutic options. PMID:30352869

Evidence Based Scoring (AI generated)