Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability.
J Immunother Cancer
; 8(1)2020 03.
Article
en En
| MEDLINE
| ID: mdl-32221012
ABSTRACT
BACKGROUND:
Microsatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection. CASE PRESENTATION An 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets.CONCLUSIONS:
The novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Vejiga Urinaria
/
Proteínas de Ciclo Celular
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Inestabilidad de Microsatélites
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Anticuerpos Monoclonales Humanizados
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Antígeno B7-H1
/
Mutación
Tipo de estudio:
Risk_factors_studies
Límite:
Aged80
/
Humans
/
Male
Idioma:
En
Revista:
J Immunother Cancer
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos