When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

Vugt, Marcel A.T.M. van; Parkes, Eileen

doi:10.1016/j.trecan.2021.12.003

Cited by 35 publications

(25 citation statements)

References 168 publications

(196 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, the PTEN loss associated underactive TIME, chemoresistance and poor prognosis in HGSC remains understudied 23,24 . Findings from our study validated the previous reports 22,25 on BRCA1 deficiency associated cytosolic abundance of dsDNA in ID8 cells and downstream constitutive activation of the cGAS-STING pathway 22 . PTEN , however, functions to dephosphorylate IRF3 and stimulates its translocation into the nucleus to begin transcription of IFN-1 genes.…”

Section: Discussionsupporting

confidence: 91%

PTEN and BRCA1 tumor suppressor loss associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in a murine model of ovarian cancer

Shakfa

Conseil

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: High grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by chemoresistance and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Loss of BRCA1 and PTEN function due to mutations or epigenetic influence have been widely associated with variable clinical outcomes, where tumors with BRCA1 mutations exhibit increased chemosensitivity and those with PTEN mutations have been reported to exhibit chemoresistance. Given the established type 1 interferon regulatory function of BRCA1 and PTEN genes and associated contrasting T cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, in this study we investigated the potential of Stimulator of Interferon Genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency. Methods: Expression of PTEN protein was evaluated in tissue microarrays generated using pre-treatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8-Trp53-/-; Pten-/- and ID8-Trp53-/-; Brca1-/-, were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy. Results: Tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intra-epithelial CD68+ macrophage infiltration as compared to intact PTEN expression. In vivo studies demonstrated that Pten deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+ MDSCs in the ascites, and reduced effector CD8+ cytotoxic T cell function compared to Brca1 deficient cells; further, tumors from mice injected with Pten deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten deficient ascites to a M1-like phenotype and rescued CD8+ cytotoxic T cell activation. Conclusions: This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN deficient HGSC.

show abstract

Section: Discussionsupporting

confidence: 91%

PTEN and BRCA1 tumor suppressor loss associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in a murine model of ovarian cancer

Shakfa

Conseil

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Germline BRCA1/2 mutations range between 9 and 21% in unselected TNBC patients ( 97 , 98 ). The presence of mutations in repair genes could lead to a greater formation of neoantigens, which would translate into an increase in immune infiltrate in these cases ( 99 – 102 ). For this reason, it is important to analyze the results of the studies considering the germinal component to avoid bias in the results.…”

Section: Discussionmentioning

confidence: 99%

Immune Lymphocyte Infiltrate and its Prognostic Value in Triple-Negative Breast Cancer

et al. 2022

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) occurs more frequently in young (<50 years) non-Hispanic black and Hispanic/Latina women. It is considered the most aggressive subtype of breast cancer, although, recently, immune infiltrate has been associated with long-term survival, lower risk of death and recurrence, and response to neoadjuvant chemotherapy. The aim of this review was to evaluate the clinical impact of the immune infiltrate in TNBC by discussing whether its prognostic value varies across different populations. A comprehensive systematic search in databases such as PubMed and Web of Science was conducted to include papers focused on tumor-infiltrating lymphocytes (TILs) in TNBC in different population groups and that were published before January 2021. TNBC patients with higher levels of TILs had longer overall survival and disease-free survival times compared with TNBC patients with low TIL levels. Similar results were observed for CD4+, CD8+ TIL populations. On the other hand, patients with high TIL levels showed a higher rate of pathological complete response regardless of the population group (Asian, European, and American). These results altogether suggest that TIL subpopulations might have a prognostic role in TNBC, but the underlying mechanism needs to be elucidated. Although the prognosis value of TILs was not found different between the population groups analyzed in the revised literature, further studies including underrepresented populations with different genetic ancestries are still necessary to conclude in this regard.

show abstract

“…Fortunately, we described some potentially actionable mutations in SHC, including NTRK1 fusions(n=1) and BRCA1/2 mutations(n=2), which may provide more treatment options in SHC. BRCA1 and BRCA2 are key regulators of DNA maintenance through homologous recombination (HR) ( 52 ). Additionally, they function in DNA crosslink repair as part of the Fanconi anemia (FA) complex and play important roles in the protection of stalled replication forks, transcription regulation, chromatin modulation, cell cycle regulation, checkpoint enforcement and telomere maintenance ( 52 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

“…BRCA1 and BRCA2 are key regulators of DNA maintenance through homologous recombination (HR) ( 52 ). Additionally, they function in DNA crosslink repair as part of the Fanconi anemia (FA) complex and play important roles in the protection of stalled replication forks, transcription regulation, chromatin modulation, cell cycle regulation, checkpoint enforcement and telomere maintenance ( 52 , 53 ). Meanwhile, DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway, and the inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits ( 52 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients

et al. 2023

View full text Add to dashboard Cite

BackgroundSarcomatoid hepatocellular carcinoma (SHC) is a rare epithelial malignancy with high invasiveness and poor prognosis. However, the molecular characteristics and main driver genes for SHC have not been determined. The aim of this study is to explore the potentially actionable mutations of driver genes, which may provide more therapeutic options for SHC.MethodsIn this study, DNA extraction and library preparation were performed using tumor tissues from 28 SHC patients. Then we used Miseq platform (Illumina) to sequence the target-enriched library, and we aligned and processed the sequencing data. The gene groups were tested for SNVs/Indels/CNVs. Tumor mutation burden (TMB) was assessed by the 425-cancer-relevant gene panel. Multivariate analysis of COX’s model was used for survival analysis (OS) of patients’ clinical characteristics.ResultThe median overall survival (OS) of the patients was only 4.4 months. TP53, TERT, and KRAS were the top three frequently mutated genes, with frequencies of 89.3%, 64.3%, and 21.4%, respectively. A considerable number of patients carried mutations in genes involved in the TP53 pathway (96%) and DNA Damage Repair (DDR) pathway (21%). Multiple potentially actionable mutations, such as NTRK1 fusions and BRCA1/2 mutations, were identified in SHCs.ConclusionsThis study shows a landscape of gene mutations in SHC. SHC has high mutation rates in TP53 pathway and DDR pathway. The potentially actionable mutations of driver genes may provide more therapeutic options for SHC. Survival analysis found that age, smoking, drinking, and tumor diameter may be independent prognostic predictors of SHC.

show abstract

When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

Cited by 35 publications

References 168 publications

PTEN and BRCA1 tumor suppressor loss associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in a murine model of ovarian cancer

PTEN and BRCA1 tumor suppressor loss associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in a murine model of ovarian cancer

Immune Lymphocyte Infiltrate and its Prognostic Value in Triple-Negative Breast Cancer

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients

Contact Info

Product

Resources

About