The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

Zhou, Pei; Wu, Xueying; Chen, Huan; Hu, Ying; Zhang, Henghui; Wu, Lijia; Yang, Ying; Mao, Beibei; Wang, Huaqing

doi:10.18632/aging.202267

Cited by 21 publications

(12 citation statements)

References 29 publications

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“…Furthermore, it is known that MSI-H CRCs harbor significantly more mutations than MSS CRCs ( 44 ). However, some of our observed mutations have not been linked to dMMR CRCs yet ( 53 , 55 ) and we could detect up to six synchronous MMR/HRR mutations in our MLH1 - /PMS2 - /MSH6 - cases, which is something we rarely observe in clinical practice in other cancer entities. Therefore, we believe our findings suggest MLH1 - /PMS2 - /MSH6 - cases to be a potential special subgroup that that is biologically distinct from dMMR cases with a loss of expression in only one functional heterodimer.…”

Section: Discussionmentioning

confidence: 50%

“…Our findings seem to be promising considering that dMMR/MSI cancers benefit from IO-therapy and as there is emerging evidence that combining PARP-inhibitors with IO-therapy is reasonable, especially in metastatic disease when there are often few other therapeutic options available: PARP-inhibitors induce double-strand breaks, which promotes neoantigen generation and tumor mutational burden – both enhancing the impact of IO-therapy ( 58 ). Furthermore, it has been already shown in a Chinese cohort that CRC patients with HRR mutations show a better survival upon IO-therapy than HRR-wildtype CRC patients ( 53 ). To exemplify this idea with regards to our cohort: Case 4 benefits greatly from Pembrolizumab therapy at the moment.…”

Section: Discussionmentioning

confidence: 98%

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Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

et al. 2022

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Immunohistochemical analysis of mismatch repair (MMR) protein expression is widely used to identify tumors with a deficient MMR (dMMR). MMR proteins (MLH1/PMS2 and MSH2/MSH6) work as functional heterodimers, which usually leads to the loss of expression in only one functional MMR heterodimer. Recently, there have been studies showing the simultaneous loss of immunoexpression in proteins of both heterodimers. Yet, this phenomenon has been rarely investigated. In this study, we retrospectively considered cases of different digestive system cancers (gastric cancer, ampullary cancer, small bowel cancer, colorectal cancer), which were immunohistochemically tested for dMMR within a 4-year period at our university hospital (n=352). Of the 103 cases showing dMMR, 5 cases (1.4% of all, 5.1% of dMMR cases) showed a concurrent loss of MLH1, PMS2 and MSH6 immunoexpression, whereas in the other 98 dMMR cases only one MMR heterodimer was affected. MLH1-/PMS2-/MSH6- cancer cases almost arose throughout the entire digestive tract: from the gastric antrum to the left colic flexur. To provide a comprehensive molecular characterization of this MLH1-/PMS2-/MSH6- immunophenotype, tumors were analyzed for microsatellite instability, MLH1 promotor hypermethylation and BRAF exon 15 status. Furthermore, we performed next-generation sequencing focusing on genes related to DNA repair. Here, we could detect pathogenic germline variants as well as multiple sporadic mutations in different genes involved in MMR and homologous recombination repair (HRR) respectively. The affected MMR/HRR-related genes were: ATM, BARD1, BRCA1, CDK12, CHEK1, CHEK2, FANCA, MLH1, MSH6, PALB2, TP53. Considering the biologic function of HRR/MMR proteins as potential drug targets and the low frequency of most of these mutations in digestive system cancers in general, their common occurrence in our MLH1-/PMS2-/MSH6- cases seems to be even more noteworthy, highlighting the need for recognition, awareness and further investigation of this unusual IHC staining pattern.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 98%

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

et al. 2022

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“…Since a tumor could become more malignant after recurrence or metastasis, the role of CD86 in this stage and the relationship with OS could be further explored. In addition, a previous study shows that the correlation between homologous recombination mutation and prognosis is inconsistent when patients are receiving different types of treatment [ 36 ]. Thus, the prognostic value of CD86 could also be explored in patients receiving ICIs, as CD86 plays a vital role in immune response.…”

Section: Discussionmentioning

confidence: 99%

Expression Pattern and Prognostic Value of CTLA-4, CD86, and Tumor-Infiltrating Lymphocytes in Rectal Cancer after Neoadjuvant Chemo(radio)therapy

Yin

Wang

Feng

et al. 2022

Cancers

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The synergistic effect of combining immune checkpoint inhibitors (ICIs) with neoadjuvant chemo(radio)therapy (nCRT) in colorectal cancer is still limited. We aimed to understand the impact of nCRT on the tumor microenvironment and to explore favorable immune markers of this combination. Herein, we investigated the expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), CD86, CD4, and CD8 after nCRT and its association with clinicopathological characteristics. Immunostaining of immune-related molecules was performed in 255 surgically resected specimens from rectal cancer patients treated with nCRT. CD4 and CD8 expression on the tumor (tCD4/CD8), stroma (sCD4/CD8), and invasive front (iCD4/CD8) was evaluated. The expression levels of immune-related molecules were significantly lower in the nCRT-treated group, except for CTLA-4 and sCD8. However, patients with higher sCD8+ cell density and CTLA-4 expression had better progression-free survival (PFS) and distant metastasis-free survival (DMFS). In addition, higher CD86 expression was associated with poorer overall survival (OS). Higher CTLA-4 expression was associated with higher tCD8+ cell density, whereas CD86 expression was correlated with the cell density of t/sCD8. Prognostic analysis confirmed that the relationships between CTLA-4 and DMFS as well as CD86 and OS were significantly correlated in low rather than high CD8+ cell density. Further the combination of CD8+ cell density and CD86 expression was shown to be an independent prognostic factor of OS, whereas the combination of CTLA-4 was not for DMFS. Together, these results demonstrate significant correlations between CD86 expression and t/sCD8+ cell density in rectal cancer after nCRT and could potentially have clinical implications for combining ICIs and nCRT.

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“…The current status of immunotherapy in the COAD eld can be simply summarized as "progress without breakthroughs". Only a few people are effective, and most patients still cannot bene t from immunotherapy [15]. Therefore, there is an urgent need to nd targets for immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the significance of DNASE1L3 in immune infiltration of colon adenocarcinoma

Chen

Zhu

Sun

et al. 2022

Preprint

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Background: Several studies have shown the crucial role of DNASE1L3 in regulating immune function in various diseases including Systemic Lupus Erythematosus (SLE) and cancers. However, the function and expression of DNASE1L3 in Colon Adenocarcinoma (COAD) remain obscure. The aim of this study was to explore the immune function of DNASE1L3 in COAD through a comprehensive bioinformatic analysis. Objective: To study DNASE1L3 expression in colorectal cancer through multiple databases. Use bioinformatics analysis to learn about the influence of this gene on clinical prognosis and immune function in colorectal cancer, and to explore its potential biological function. Methods: We obtained transcriptome data of COAD and normal samples from The Cancer Genome Atlas (TCGA) and identified differentially expressed (DE) mRNAs. The difference mRNA between COAD and normal samples and the difference mRNA between stage I and stage IV were respectively excavated, and then the intersection was taken. DNASE1L3 was determined the significant DE mRNA. Further, we obtained the different expressions of DNASE1L3 integrates the normal tissue data in the TCGA tumor tissue data to analyze the expression differences of 20 tumors.DNASE1L3 was further subjected to an analysis of expression in a different stage of COAD. We evaluated the influence of DNASE1L3 on clinical prognosis using Gene Expression Profiling Interactive Analysis (GEPIA) in COAD patients. To demonstrate the relationship between immune function and DNASE1L3, we investigated whether DNASE1L3 expression is related to the level of immune infiltration in COAD. We separately counted the number of neoantigens in COAD and analyzed the relationship between DNASE1L3 expression and the number of antigens. we analyzed the correlation between DNASE1L3 expression and MSI (microsatellite instability), using Spearman's rank correlation coefficient. In addition, we analysis the enrichment function of DNASE1L3.Finally, we performed immunohistochemical analysis on tissue microarray of colon adenocarcinoma. Results: In this study, we observed significantly down-regulated expression of DNASE1L3 in many different cancers including COAD, which also correlated with grade. Low expression of DNASE1L3 was significantly correlated with poorer overall survival (OS) in COAD (OS HR = 0.4, P=0.032). Low expression of DNASE1L3 was found with a poor prognosis. DNASE1L3 expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, B cells, macrophages, neutrophils and dendritic cells (DCs) in COAD. DNASE1L3 expression showed strong correlations with diverse immune marker sets in COAD. Enrichment functional analysis revealed that DNASE1L3 was associated with immunoglobulin complexes, antibacterial humoral responses, and humoral immune responses. Conclusions: These findings suggest that DNASE1L3, which functions as a tumor suppressor gene in COAD, might be a potential therapeutic target. It is correlated with prognosis and immune infiltrating levels, including those of CD4+ T and CD8+ T cells, B cells, macrophages, neutrophils and dendritic cells (DCs) in COAD patients. These findings suggest that DNASE1L3 can be used as a prognostic biomarker for determining prognosis and immune infiltration in COAD. These findings suggest that DNASE1L3 can be used as a prognostic biomarker for determining prognosis and immune infiltration in COAD.

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The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses

Cited by 21 publications

References 29 publications

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

Expression Pattern and Prognostic Value of CTLA-4, CD86, and Tumor-Infiltrating Lymphocytes in Rectal Cancer after Neoadjuvant Chemo(radio)therapy

Analysis of the significance of DNASE1L3 in immune infiltration of colon adenocarcinoma

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