Association of<i>MUC16</i>Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors

Zhang, Lei; Han, Xiaohong; Shi, Yuankai

doi:10.1001/jamanetworkopen.2020.13201

Cited by 65 publications

(56 citation statements)

References 39 publications

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“…35,36 A recent study indicated that the mutational frequency of MUC16 is 42.76% in lung adenocarcinoma, and 38.84% in lung squamous cell carcinoma, respectively. 37 Patients with MUC16 mutation have been found to have CD8A and PD-L1 positive is also higher in MUC16 mutated cases than in wild-type mutations. In addition, patients with MUC16 mutation receiving ICI treatment have also been associated with superior outcomes.…”

Section: Discussionmentioning

confidence: 97%

“…This protein, thought to be the precursor of CA125 used as a biomarker for ovarian cancer, has been found to suppress the natural killer cell function which regulates tumor cell proliferation, metastasis and innate immune response 35,36 . A recent study indicated that the mutational frequency of MUC16 is 42.76% in lung adenocarcinoma, and 38.84% in lung squamous cell carcinoma, respectively 37 . Patients with MUC16 mutation have been found to have significantly elevated TMB compared to those without them.…”

Section: Discussionmentioning

confidence: 99%

“… 35 , 36 A recent study indicated that the mutational frequency of MUC16 is 42.76% in lung adenocarcinoma, and 38.84% in lung squamous cell carcinoma, respectively. 37 Patients with MUC16 mutation have been found to have significantly elevated TMB compared to those without them. CD8A and PD‐L1 positive is also higher in MUC16 mutated cases than in wild‐type mutations.…”

Section: Discussionmentioning

confidence: 99%

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Novel genetic characteristics in low‐grade fetal adenocarcinoma of the lung

et al. 2021

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Background Low‐grade fetal adenocarcinoma of the lung (L‐FLAC) is a rare subtype of lung adenocarcinoma with undetermined histological features and genetic abnormalities. In this study, we attempted to investigate the pathological characteristics and genomic profiles of L‐FLAC. Methods Among 9839 cases of primary lung adenocarcinoma resected at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2011 and June 2016, three cases diagnosed with L‐FLAC were selected. An immunohistochemical profile and whole exome sequencing (WES) using tumor and normal tissues was conducted. The last follow‐up date of patients was January 2021. Results Three cases diagnosed with L‐FLAC were finally screened, suggesting a percentage of 0.03%. All three patients were male and diagnosed as stage I following radical lobectomy. The missense variant was found to be the major gene mutation type using WES. CTNNB1 and DICER1 were the two most frequent gene mutations. All cases demonstrated positive TTF‐1 expression. In addition, two patients showed positive expression of β‐catenin (nuclear/cytoplasmic expression), CgA and Sny. Negative expression of PD‐L1 in tumor cells was observed in all three cases. One case with a relatively high tumor mutation burden (TMB) (2.18 mut/Mb) had an inferior overall survival of 11.5 months. However, the other two cases with a lower TMB (0.12 and 0.74 mut/Mb) still acquired disease‐free status up to the last follow‐up date. Conclusions L‐FLAC has a specific molecular background which is different from lung adenocarcinoma. Furthermore, gene heterogeneity was found and might be the reason for a dramatically different prognosis in these L‐FLAC patients.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

“… 35 , 36 A recent study indicated that the mutational frequency of MUC16 is 42.76% in lung adenocarcinoma, and 38.84% in lung squamous cell carcinoma, respectively. 37 Patients with MUC16 mutation have been found to have significantly elevated TMB compared to those without them. CD8A and PD‐L1 positive is also higher in MUC16 mutated cases than in wild‐type mutations.…”

Section: Discussionmentioning

confidence: 99%

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Novel genetic characteristics in low‐grade fetal adenocarcinoma of the lung

et al. 2021

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“…In addition, the decreased somatic mutation rate of MUC16 and the increased rate of TTN somatic mutations were significant features of CB. A recent study has shown that MUC16 mutations may be related to the efficacy of ICI therapy and to the improvement of prognosis-related genomic factors in solid tumors [ 34 ]. A possible mechanism for this is that MUC16 binds to the Siglec 9 receptor on NK cells, downregulating their cytotoxicity and thereby allowing tumor cells to escape immune surveillance [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Multi-omic analyses of hepatocellular carcinoma to determine immunological characteristics and key nodes in gene-expression network

Wang

Zhang

2021

Bioscience Reports

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Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide, but effective immunotherapy is still limited for those affected. Therefore, there is an urgent need to explore the specific mechanisms governing tumor immunity to improve the survival rate for those diagnosed with HCC. In this study, we performed a new immune stratification of HCC samples into two subclasses (A and B) from The Cancer Genome Atlas and the International Cancer Genome Consortium databases, and comprehensive multi-omic analyses of major histocompatibility complex genes, gene copy-number variations, somatic mutations, DNA methylation, and non-coding RNAs. Subclass A was found to have a higher survival rate compared to subclass B, and there were significant immunological differences between the two clusters. Based on these differences, we identified DRD1 and MYCN as key hub genes in the immune-phenotype gene expression regulatory network. These results provide novel ideas and evidence for HCC regulatory mechanisms that may improve immunotherapy for this cancer.

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“…A previously published pan-cancer analysis of 30 solid tumor types showed that patients with MUC16 mutations showed higher tumor mutation burden and neoantigen burden, indicating increased tumor immunogenicity, which can predict immune checkpoint inhibitor treatment response. The study included 397 cases of glioblastoma and 61 of these cases (15.37%) showed MUC16 mutations [14]. Therefore, we wondered whether the MUC16 mutation in G34-DHGs might also be associated with immune in ltration.…”

Section: Muc16 Mutation and Immune In Ltration Characteristics Of G34-dhgsmentioning

confidence: 99%

High Frequency of PDGFRA and MUC Family Gene Mutations in Diffuse Hemispheric Glioma, H3 G34-mutant: A Glimmer of Hope?

Duan

Zhong

et al. 2021

Preprint

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BackgroundDiffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA). MethodsHematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data.ResultsWES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months. ConclusionsOur results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.

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Association ofMUC16Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors

Cited by 65 publications

References 39 publications

Novel genetic characteristics in low‐grade fetal adenocarcinoma of the lung

Novel genetic characteristics in low‐grade fetal adenocarcinoma of the lung

Multi-omic analyses of hepatocellular carcinoma to determine immunological characteristics and key nodes in gene-expression network

High Frequency of PDGFRA and MUC Family Gene Mutations in Diffuse Hemispheric Glioma, H3 G34-mutant: A Glimmer of Hope?

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