DDR

In the DDR-wild-type cohort, independent factors predicting longer OS were IO therapy (compared with each other treatment group: vs. IO+non-IO combinations, p = 0.003; vs. chemotherapy, p < 0.001; vs. anti-DDR agents, p < 0.001; vs. other targeted therapies, p = 0.006), absence of liver metastases (p < 0.001), and normal albumin (p < 0.001) and lactate dehydrogenase (p = 0.001) levels. Prospective studies are warranted to refine the role of DDR alterations as biomarkers of IO response.

The ATR inhibitor also markedly sensitized NBS1 mutants to Etoposide, suggesting that ATR functions as a compensatory pathway in the absence of functional NBS1 during specific types of DNA damage. Collectively, our findings establish valuable NBS1-deficient Chinese hamster cell models that expand understanding of NBS1 function and highlight their utility for investigating DNA repair deficiencies and developing targeted therapeutic approaches for chromosomal instability disorders and cancers with NBS1 mutations.

The CpG-mediated NF-κB activation results in the release of immuno-stimulating cytokines that promote an antitumoral response. As we previously established that G34-mutant DHGs are characterized by DNA repair impairment, we combined CpG dinucleotides with a PARP (poly (ADP-ribose) polymerase) inhibitor, olaparib, in the HDL nanoparticles.

BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

In vitro validation using WRN inhibitors demonstrated potent suppression of malignant phenotypes (proliferation, clonogenicity, migration, invasion) in colorectal, endometrial, and ovarian cancer models. Our study suggests that WRN plays a role in cancer diagnosis and therapy, especially in cancers characterized by replicative stress or defective DNA damage repair, and that WRN can serve as a potential target for cancer immunotherapy or targeted therapies and as a prognostic marker for certain tumors.

BPA-BNCT exerts potent and selective antitumor effects against cervical cancer through a dual mechanism: LAT1-mediated boron delivery ensures tumor specificity, while the resulting high-linear energy transfer radiation induces DNA damage that capitalizes on the inherent limitations of the tumor cells' DNA repair capacity, leading to catastrophic cell death. The therapy demonstrates a distinct advantage in treating adenocarcinoma subtypes, which are typically less responsive to conventional radiotherapy. These findings provide robust preclinical evidence supporting BNCT as a promising therapeutic approach, particularly for radiotherapy-resistant cervical adenocarcinoma.

Using publicly available panel sequencing data, we find that ERCC2 wild type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared to ERCC2 WT cases with low levels of the signature. We also find that other solid tumor types with ERCC2 mutations also show the characteristic mutational signature seen in NER-deficient ERCC2 -mutant bladder cancers, suggesting a novel approach to therapeutically target these ERCC2 -mutant solid tumors beyond bladder cancer.

Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

This case demonstrates that synchronous lung cancers may result from the combined effects of carcinogen-induced field cancerization and DNA repair deficiencies. The identification of PMS2 and ERCC2 alterations provides mechanistic evidence of genetic vulnerability, highlighting the importance of counseling, surveillance, and potential DNA repair-targeted strategies.

Our findings highlight the value of combining dermatological, radiological, and molecular assessments for accurate diagnosis and counseling. The recurrence of the same variant in unrelated families from one region suggests a founder effect.

These cases represent the first definitive report of cranial RIS following glioma chemoradiation therapy in patients with LFS. The short latency and aggressive nature of these tumors at the irradiated site highlight the need for proactive follow-up in patients with LFS after chemoradiation therapy to screen for RIS and improve outcomes through timely intervention. https://thejns.org/doi/10.3171/CASE25588.