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Ref Type Journal Article
PMID (26674132)
Authors Castro MP, Goldstein N
Title Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations.
Journal Vol Issue Date Pages Journal Short Title
Journal for immunotherapy of cancer 3 2015 58 J Immunother Cancer
URL
Abstract Text Mismatch repair deficiency (MMRD) is a common pathway of malignant transformation accounting for approximately 15-20 % of human carcinogensis. It has been postulated that MMRD increases tumor antigenicity and highlights a role for immunotherapeutic approach MMR-deficient cancers. This strategy was pursued in a patient with upper tract urothelial carcinoma, and the results are reported here.Molecular profiling was performed using next generation DNA sequencing and (IHC) testing for MMR and PD-L1. A patient with sporadic, high grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy, and 340 VUS alterations. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6 as well as deleterious mutations in these genes. IHC staining for programmed cell death ligand-1 [PD-L1] revealed 2+ staining in 80 % of cells. The patient gained access to combination immunotherapy trial utilizing MEDI4736 and MEDI0680 through a clinical trial. The patient achieved a prolonged, complete remission within two months and had no severe ill effects from the treatment.Given their ability to generate neo-antigens, MMR-deficient cancers may be uniquely susceptible to immune checkpoint inhibitor strategies, including urothelial tract cancers. Screening for MMR deficient cancers has the potential to become a routine strategy for evaluating the role of PD-L1 inhibitors for patient with advanced disease. (Clinicaltrials.gov NCT00938834. Registered 13 July 2009).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK2 D319N missense unknown JAK2 D319N lies within the FERM domain of the Jak2 protein (UniProt.org). D319N has been identified in sequencing studies (PMID: 26674132, PMID: 24755471), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Sep 2025).
MSH2 A913fs frameshift unknown MSH2 A913fs results in a change in the amino acid sequence of the Msh2 protein beginning at aa 913 of 934, likely resulting in premature truncation of the functional protein (UniProt.org). A913fs is associated with loss of Msh2 expression in patient samples (PMID: 26674132), but has not been fully biochemically characterized and therefore, its effect on Msh2 protein function is unknown.
MSH6 R361H missense unknown MSH6 R361H lies within an MSH2-binding region of the Msh6 protein (PMID: 12019211). R361H has been identified in the scientific literature (PMID: 26674132, PMID: 25344691, PMID: 31555481), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, Oct 2025).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CD274 pos MSH2 E226* MSH2 E580* MSH2 A913fs MSH2 neg MSH6 R361H MSH6 neg renal pelvis transitional cell carcinoma predicted - sensitive Durvalumab + MEDI0680 Case Reports/Case Series Actionable In a Phase I trial, treatment with the combination of Imfinzi (durvalumab) and MEDI0680 (AMP-514) resulted in a complete response ongoing for at least 11 months in a patient with metastatic MSH2 and MSH6-negative, CD274 (PD-L1)-positive renal pelvis urothelial carcinoma harboring MSH2 A913fs, E226*, and E580*, and MSH6 R361H (PMID: 26674132; NCT02118337). 26674132