Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma

npj Precision Oncology, Год журнала: 2024, Номер 8(1)

Опубликована: Фев. 3, 2024

Abstract The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study 803 patients with PDAC (42% metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that status and subtypes were prognostic ( p < 0.001). Relative wildtype tumors (median OS 38 months), G12R had similar 34 while Q61 G12D mutated shorter 20 months [HR: 1.9, 95% CI 1.2–3.0, = 0.006] 22 1.7, 1.3–2.3, 0.001], respectively). There was enrichment (34% vs 24%, OR: 1.2–2.4, 0.001) well moderately differentiated (14% 9%, 1.05–2.99, 0.04). Similar findings observed the external validation cohort (PanCAN’s Know Your Tumor® dataset, n 408).

Язык: Английский

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The molecular code of kidney cancer: A path of discovery for gene mutation and precision therapy

Molecular Aspects of Medicine, Год журнала: 2025, Номер 101, С. 101335 - 101335

Опубликована: Янв. 1, 2025

Renal cell carcinoma (RCC) is a malignant tumor with highly heterogeneous and complex molecular mechanisms. Through systematic analysis of TCGA, COSMIC other databases, 24 mutated genes closely related to RCC were screened, including VHL, PBRM1, BAP1 SETD2, which play key roles in signaling pathway transduction, chromatin remodeling DNA repair. The PI3K/AKT/mTOR particularly important the pathogenesis RCC. Mutations such as PIK3CA, MTOR PTEN are associated metabolic abnormalities proliferation. Clinically, mTOR inhibitors VEGF-targeted drugs have shown significant efficacy personalized therapy. Abnormal regulation reprogramming, especially glycolysis glutamine pathways, provides cells continuous energy supply survival advantages, GLS1 promising results preclinical studies. This paper also explores potential immune checkpoint combination targeted drugs, well application nanotechnology drug delivery In addition, unique mechanisms revealed individualized therapeutic strategies explored for specific subtypes TFE3, TFEB rearrangement type SDHB mutant type. review summarizes common gene mutations their mechanisms, emphasizes diagnosis, treatment prognosis, looks forward prospects multi-pathway therapy, immunotherapy treatment, providing theoretical support clinical guidance new development.

Язык: Английский

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Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

British Journal of Cancer, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Abstract Background Prostate cancer (PC) is the commonest male visceral cancer, and second leading cause of mortality in men Western world. Methods Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen Probasin Cre-Recombinase ( Pb-Cre ) Pten -deficient mouse model PC, we identified Arid1a loss as driver development metastatic disease. Results The insertion transposon gene resulted 60% reduction expression, reduced tumour free survival SB:Pten fl/fl INT median 226 days vs WT 293 days, p = 0.02),with elevated rates metastasis 75% lung rate 17% , < 0.001). We further generated - model, which demonstrated profound acceleration tumorigenesis mice compared to alone +/+ 267 103 0.0001). Conclusion Our data revealed homozygous required dramatically accelerate prostate tumourigenesis. Analysis RNA ChIP -Sequencing suggests enhanced function AP-1 subunit cFos. In clinical PC cohort, ARID1A cFos levels stratified an aggressive subset with poor outcome only 30 months.

Язык: Английский

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Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment

Cancer Research, Год журнала: 2024, Номер 84(7), С. 965 - 976

Опубликована: Янв. 24, 2024

Abstract Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators tumor-intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations inhibitors. Some success has observed early clinical studies combined immunotherapy agents targeting DNA methylation histone modification; however, less is known about chromatin remodeler-targeted therapies. Here, we provide discussion on regulation tumor immunogenicity by remodeling SWI/SNF complex through multiple associated broadly include IFN signaling, damage, mismatch repair, oncogenic programs, polycomb-repressive antagonism. Context-dependent subunits can elicit opportunities synthetic lethality reduce T-cell exhaustion. In summary, alongside significance predicting outcomes, their ability modulate landscape offers intervention.

Язык: Английский

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Developments in Genetics: Better Management of Ovarian Cancer Patients

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(21), С. 15987 - 15987

Опубликована: Ноя. 5, 2023

The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing properly classify all ovarian cancers. In article, we address statistics, histopathological classification, pathways implicated cancer, screening panels, details about genes, also candidate genes. We hope bring information medical field so as better prevent diagnose cancer.

Язык: Английский

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DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities

Cancers, Год журнала: 2023, Номер 15(2), С. 448 - 448

Опубликована: Янв. 10, 2023

The DNA damage response (DDR), a set of signaling pathways for detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these strongly associated with cancer development, including ovarian (OC), the most lethal gynecologic malignancy. In OC, failures DDR have been related not only onset but also progression chemoresistance. It is known that approximately half frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects double-strand break (DSB) repair by homologous recombination (HR), current evidence indicates probably all HGSCs harbor defect at least one pathway. These restricted HGSCs; mutations

Язык: Английский

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Molecular Profile of Intrahepatic Cholangiocarcinoma

International Journal of Molecular Sciences, Год журнала: 2023, Номер 25(1), С. 461 - 461

Опубликована: Дек. 29, 2023

Intrahepatic cholangiocarcinoma (ICC) is a relatively uncommon but highly aggressive primary liver cancer that originates within the liver. The aim of this study to review molecular profile intrahepatic and its implications for prognostication decision-making. This comprehensive characterization ICC tumors sheds light on disease’s underlying biology offers foundation more personalized treatment strategies. narrative prognostic therapeutic role ICC. Knowing helps determine prognosis support certain target therapies. panel in select patients specific therapies, predict responses, monitor responses. Precision medicine can promote improvement reduce unnecessary toxicity might have significant management following years. main mutations are tumor protein p53 (TP53), Kirsten rat sarcoma virus (KRAS), isocitrate dehydrogenase 1 (IDH1), AT-rich interactive domain-containing 1A (ARID1A). rate varies significantly each population. Targeting TP53 KRAS challenging due natural characteristics these genes. Different stages clinical studies shown encouraging results with inhibitors mutated IDH1 therapy ARID1A downstream effectors. Fibroblast growth factor receptor 2 (FGFR2) fusions an important Immune checkpoint blockade be applied small percentage patients. Molecular profiling represents groundbreaking approach understanding managing complex cancer. As our comprehension ICC’s intricacies continues expand, so does potential offering precise effective treatments. integration into practice signifies dawn new era care, emphasizing ongoing battle against malignancy.

Язык: Английский

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Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

Cells, Год журнала: 2023, Номер 12(6), С. 952 - 952

Опубликована: Март 21, 2023

Epigenetic remodeling and metabolic reprogramming, two well-known cancer hallmarks, are highly intertwined. In addition to their abilities confer cell growth advantage, these alterations play a critical role in dynamically shaping the tumor microenvironment antitumor immunity. Recent studies point toward interplay between epigenetic regulation rewiring as potentially targetable Achilles’ heel cancer. this review, we explore key mechanisms that underpin immunomodulatory of AT-rich interaction domain 1A (ARID1A), most frequently mutated regulator across human cancers. We will summarize recent advances targeting ARID1A-deficient cancers by harnessing immune-metabolic vulnerability elicited ARID1A deficiency stimulate immune response, ultimately, improve patient outcome.

Язык: Английский

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The Clinical, Genomic, and Transcriptomic Landscape of BRAF Mutant Cancers

Cancers, Год журнала: 2024, Номер 16(2), С. 445 - 445

Опубликована: Янв. 19, 2024

BRAF mutations are classified into four molecularly distinct groups, and Class 1 (V600) mutant tumors treated with targeted therapies. Effective treatment has not been established for 2/3 or Fusions. We investigated whether mutation class differed according to clinical, genomic, transcriptomic variables in cancer patients.

Язык: Английский

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Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis)

Cell Death and Disease, Год журнала: 2024, Номер 15(5)

Опубликована: Май 29, 2024

Abstract ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in various cancer types and has emerged as potential therapeutic target. In this study, we observed that ARID1A-deficient colorectal (CRC) cells showed synthetic lethal effects with p53 activator, RITA (reactivating inducing tumor apoptosis). RITA, an inhibitor p53-MDM2 interaction, exhibits increased sensitivity compared to ARID1A wild-type cells. Mechanistically, lethality dependent on both activation DNA damage accumulation, which are regulated by interplay between RITA. loss opposing effect targets, leading decreased p21 expression levels proapoptotic genes, PUMA NOXA, further potentiated treatment, ultimately cell apoptosis. Meanwhile, aggravates RITA-induced accumulation downregulating Chk2 phosphorylation. Taken together, significantly heightens CRC, revealing novel interaction These findings present promising approach for characterized loss-of-function mutations.

Язык: Английский

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