Biology subjects

Szallasi, Z.

Publications and source records attributed to Szallasi, Z..

16 recordsLinked to original sources

bioRxiv2026

Identification of an ERCC2 mutation associated mutational signature of nucleotide excision repair deficiency in targeted panel sequencing data

Next generation sequencing based mutational signatures are frequently used to identify tumors with specific DNA repair deficiencies for targeted therapeutic strategies. Although mutational signatures are most commonly derived from whole exome (WES) or whole genome sequencing (WGS) data, more patients currently undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data. Here, we derive and validate a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating ERCC2 mutations in bladder cancer. 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.

bioinformatics↗

bioRxiv2026

Zero-shot biological reasoning with open-weights large language models reproduces CRISPR screen based prediction of synthetic lethal interactions.

Identifying clinically relevant synthetic lethal interactions has great potential for uncovering novel therapeutic vulnerabilities in cancer. Current approaches rely on machine learning models that estimate probabilities of synthetic lethal interactions, without supplying explicit knowledge of the underlying biology and lack the human-readable interpretation leading to the prediction. Large Language Models (LLMs) represent a new class of tools capable of reasoning and leveraging extensive biological knowledge acquired from relevant literature during their pretraining. Here, we tested multiple open-weight LLMs for their ability to predict known and novel synthetic lethal interactions. We found that most of the tested models were better at reconstructing the results of three known genome-wide CRISPR knockout screens than random chance and non-LLM-based methods, and observed that their performance was related to the parameter-size of the model, and on average benefited little from additional pathway and genetic information apart from what they already possess when estimating the likelihood of a synthetic lethal relationship. After selecting the model that offered the best balance of predictive performance and computational efficiency for our use case (Qwen2.5-32B-Instruct, 0.715 AUROC), we performed an in silico screen of 398,277 gene pairs from 893 clinically relevant genes. Our goal was to highlight the potential of open-weights LLMs as scalable, context-aware prioritization tools for synthetic lethal interactions, and to lay the groundwork for predicting higher-order genetic interactions.

bioinformatics↗

bioRxiv2025

Microenvironmental information significantly improves the recognition of cell types in human lung cancer patients

Accurate single-cell phenotypic classification in histopathological tissue sections is essential for understanding tumor behavior, identifying potential therapeutic targets, and improving prognostic assessments in cancer research. In this study, we applied deep learning to classify lung cancer cell phenotypes in hematoxylin and eosin-stained tissue sections. Using 11 whole slide images from 11 patients, we annotated nearly 20,000 cells into seven distinct phenotypes for training and validation. We used a fisheye transformation technique, which modifies images to mimic fisheye camera effects in order to incorporate cellular microenvironment information to enhance deep learning models. We evaluated its effectiveness on lung cancer tissue sections, optimizing transformation parameters and assessing classification performance through multiple cross-validation strategies. Our results demonstrate that the transformation significantly improves classification accuracy, approaching human level performance, particularly for phenotypes that rely on subtle morphological differences. The approach enhances model generalizability across patient samples, highlighting the importance of integrating spatial context in computational pathology. These findings suggest that incorporating adaptive image transformations can significantly improve automated histopathological analysis, with potential implications for more robust and clinically applicable AI-driven diagnostics.

bioinformatics↗

bioRxiv2023

Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.

Gastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD). Moreover, high expression of DNA damage marker H2AX correlated with CIN, WGD, and inferior patient survival. By developing and implementing a composite diagnostic score that incorporates TP53 mutation status, ploidy abnormalities, and H2AX expression, among other genomic information, we can identify GEA cell lines with enhanced sensitivity to DDR pathway inhibitors targeting Chk1/2 and Wee1. Anti-tumor properties were further augmented in combination with irinotecan (SN38) but not gemcitabine chemotherapy. These results implicate specific DDR biomarkers and ploidy abnormalities as diagnostic proxy that may predict premalignant progression and response to DDR pathway inhibitors.

cancer biology↗

bioRxiv2023

Analysis of evolutionary dynamics and clonal architecture in prostate cancer

The extent to which clinical and genomic characteristics associate with prostate cancer clonal architecture, tumor evolution, and therapeutic response remains unclear. Here, we reconstructed the clonal architecture and evolutionary trajectories of 845 prostate cancer tumors with harmonized clinical and molecular data. We observed that tumors from patients who self-reported as Black had more linear and monoclonal architectures, despite these men having higher rates of biochemical recurrence. This finding contrasts with prior observations relating polyclonal architecture to adverse clinical outcomes. Additionally, we utilized a novel approach to mutational signature analysis that leverages clonal architecture to uncover additional cases of homologous recombination and mismatch repair deficiency in primary and metastatic tumors and link the origin of mutational signatures to specific subclones. Broadly, prostate cancer clonal architecture analysis reveals novel biological insights that may be immediately clinically actionable and provide multiple opportunities for subsequent investigation. Statement of significanceTumors from patients who self-reported as Black demonstrate linear and monoclonal evolutionary trajectories yet experience higher rates of biochemical recurrence. In addition, analysis of clonal and subclonal mutational signatures identifies additional tumors with potentially actionable alterations such as deficiencies in mismatch repair and homologous recombination.

cancer biology↗

bioRxiv2023

Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.

PurposeDue to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. Experimental DesignWe used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. ResultsFunctional assays showed NER deficiency in ccRCC cells. Irofulven sensitivity increased in some cell lines. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ConclusionsccRCC cell line based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells. Translational relevanceDNA repair deficiencies can be therapeutically targeted by synthetic lethal-based strategies in cancer. However, clear cell renal cell carcinoma (ccRCC) has not benefitted from this therapeutic approach due to a lack of evidence for the presence of specific DNA repair pathway deficiencies. Here, we demonstrate that ccRCC harbors a therapeutically targetable DNA repair pathway aberration, nucleotide excision repair (NER) deficiency. ccRCC cell lines displayed robust signs of NER deficiency as determined by functional assays and some of these cell lines also displayed NER deficiency induced mutational signatures. These cell lines are also sensitive to irofulven, an abandoned anticancer agent that creates DNA lesions which can only be repaired by the NER pathway. We estimate that up to 10% of ccRCC cases may respond to NER-directed therapy with irofulven based on NER deficiency associated mutational signatures and PTGR1 expression levels, which is an enzyme required to activate irofulven.

cancer biology↗

bioRxiv2022

Diagnostic tool to identify and treat DNA repair deficient gastroesophageal adenocarcinomas

Background and aimsDNA repair deficiency is a common feature of cancer. Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in solid tumors. HR deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of DNA repair pathway deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Furthermore, whether DNA repair deficient GEA have enhanced responsiveness to platinum chemotherapy and sensitivity to PARP inhibitors is not well characterized. MethodsUsing whole exome and genome sequencing data, we measured various HR deficiency-associated mutational signatures in patient specimen of gastric, esophageal and colorectal cancer specimens and gastric cancer cell lines. Gold-standard immunofluorescence assays were used to confirm HR and NER deficiency in cancer cell lines. The relationship between PARP inhibitor treatment and tumor response was evaluated in patients with gastric cancer. Drug sensitivity was determined using standard in vitro cell culture assays. Single-cell RNA-sequencing was performed to evaluate gastric cancer response to commonly used chemotherapeutics. ResultsWe found that a significant subset of GEA, but very few colorectal tumors, show evidence of HR deficiency by mutational signature analysis (HRD score). Gastric cancer cell lines with high HRD mutational signature scores demonstrated functional HR deficiency by RAD51 assay and increased sensitivity to platinum and PARP inhibitors. There was a positive association between HRD scores and tumor response in patients with gastric cancer treated with a PARP inhibitor on a clinical trial. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by DDB2 proteo-probe assay. Single-cell RNA-sequencing revealed that, in addition to inducing general apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, which may explain the outlier sensitivity. ConclusionA subset of upper gastrointestinal tumors have genomic features of HR and NER deficiency and therefore may be more likely to benefit from platinum chemotherapy and PARP inhibition.

cancer biology↗

bioRxiv2022

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Prostate cancer (PCa) harboring BRCA1/2 mutations is often exquisitely sensitive to PARP inhibition. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibitors (PARPis). Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient PCa cell lines and identify novel genes whose loss has a profound impact on PARPi sensitivity and resistance. Specifically, MMS22L deletion, frequently observed (up to 14%) in PCa, renders cells hypersensitive to PARPis by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARPis in PCa cells through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARPi resistance caused by CHEK2 loss. Our findings may inform the use of PARPis beyond BRCA1/2-deficient tumors and support reevaluation of currently used biomarkers for PARPi treatment in PCa.

cancer biology↗

bioRxiv2021

RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer

Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 re-sensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic testing to determine who may benefit from PARP inhibition. Finally, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss.

cancer biology↗

bioRxiv2021

A Network Propagation Approach to Prioritize Long Tail Genes in Cancer

IntroductionThe diversity of genomic alterations in cancer pose challenges to fully understanding the etiologies of the disease. Recent interest in infrequent mutations, in genes that reside in the "long tail" of the mutational distribution, uncovered new genes with significant implication in cancer development. The study of these genes often requires integrative approaches with multiple types of biological data. Network propagation methods have demonstrated high efficacy in uncovering genomic patterns underlying cancer using biological interaction networks. Yet, the majority of these analyses have focused their assessment on detecting known cancer genes or identifying altered subnetworks. In this paper, we introduce a network propagation approach that entirely focuses on long tail genes with potential functional impact on cancer development. ResultsWe identify sets of often overlooked, rarely to moderately mutated genes whose biological interactions significantly propel their mutation-frequency-based rank upwards during propagation in 17 cancer types. We call these sets "upward mobility genes" (UMGs, 28-83 genes per cancer type) and hypothesize that their significant rank improvement indicates functional importance. We report new cancer-pathway associations based on UMGs that were not previously identified using driver genes alone, validate UMGs role in cancer cell survival in vitro--alone and compared to other network methods--using extensive genome-wide RNAi and CRISPR data repositories, and further conduct in vitro functional screenings resulting the validation of 8 previously unreported genes. ConclusionOur analysis extends the spectrum of cancer relevant genes and identifies novel potential therapeutic targets.

bioinformatics↗

bioRxiv2019

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

BackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.\n\nTo identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.\n\nHRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.\n\nResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.\n\nConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

cancer biology↗

bioRxiv2019

Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria

We developed an engineered bacterium based, RNA interference mediated therapeutic method to significantly reduce the symptoms in the most frequently used animal model of inflammatory bowel disease. This transkingdom RNA interference strategy was based on the non-pathogenic E. coli MDS42 strain, which was engineered to constitutively produce invasin and histeriolysin cytolysin. These proteins enabled the bacteria first to invade the colon epithelium and then degrade in the phagosome. This allowed the delivery of a plasmid encoding shRNA targeting TNF alpha into the cytoplasm of the target cells. The expression levels of TNF alpha and other cytokines significantly decreased and the inflammatory symptoms were significantly reduced. With further safety modifications this method could serve as a safe and side-effect free alternative to biologicals targeting TNF-alpha.

synthetic biology↗

bioRxiv2019

A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic aberration based molecular signatures

BackgroundConsistent with their assumed mechanism of action, PARP inhibitors show significant therapeutic efficacy in breast, ovarian and prostate cancer, which are the solid tumor types most often associated with the loss of function of key homologous recombination genes. It remains unknown, however, how frequent homologous recombination deficiency (HRD) is in other solid tumor types. Since it is well established, that HRD induces specific DNA aberration profiles and genomic scars that can be captured by various next-generation sequencing (NGS) based biomarkers, it is possible to assess the presence or absence of this DNA repair pathway aberration in any given tumor biopsy. MethodsWe derived the various HRD associated mutational signatures from whole genome and whole exome sequencing data in the lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) cases from TCGA, in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy and in lung cancer cell lines. ResultsWe have found evidence that a subset of the investigated cases shows robust signs of HR deficiency, some of which exhibiting similar patterns to those with a complete loss of function of either BRCA1 or BRCA2 genes, however, without any signs of genetic alterations being present in either of those genes. The extreme platinum responder case also showed a robust HRD associated genomic mutational profile. HRD associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. ConclusionsLung cancer cases with high levels of HRD associated mutational signatures could be candidates for PARP inhibitor treatment, and in general, the prioritization of patients for clinical trials might be achieved using the combined analysis of the HRD-related next-generation sequencing-based mutational signatures.

cancer biology↗

bioRxiv2018

Influence of mutagenic versus non-mutagenic pre-operative chemotherapy on the immune infiltration of breast cancer

BackgroundChemotherapeutic agents are often mutagenic. Induction of mutation associated neo-epitopes is one of the mechanisms by which chemotherapy is thought to increase the number of tumor-infiltrating lymphocytes, but the clinical relevance of this triggered immune response is not known.\n\nWe decided to investigate, whether treatment with various chemotherapeutic agents with significantly different mutagenic capacity induce a significantly different number of stromal tumor-infiltrating lymphocytes (StrTIL) in the clinical setting.\n\nMethods112 breast carcinoma cases treated with pre-operative chemotherapy were selected for the study. According to chemotherapy regimen 28/112 patients received platinum-based, 42/112 cyclophosphamide-based and 42/112 anthracycline-based chemotherapy. The percentage of stromal tumor-infiltrating lymphocytes (StrTIL) was evaluated on hematoxylineosin stained slides of pre-treatment core biopsy (pre-StrTIL) and post-treatment surgical tumor samples (post-StrTIL), according to the most recent recommendation of International TILs Working Group. In survival analyses, TIL changes ({Delta}StrTIL) were calculated from the difference between post-StrTIL and pre-StrTIL.\n\nResultsOf the 112 cases, 58.0% (n=65) were hormone receptor (HR) positive and 42.0% (n=47) were HR negative. There was a trend of higher post-StrTIL compared to pre-StrTIL (median 6.25% vs. 3.00%; p<0.001). When analyzing the pre-StrTIL and post-StrTIL among the three treatment groups, we experienced significant StrTIL increase independently of the treatment applied. Based on the results of survival analyses both post-StrTIL and {Delta}StrTIL was found to be independent prognostic factor in HR negative cases. Each 1% increase in post-StrTIL reduced the hazard of distant metastases development by 2.6% (hazard ratio: 0.974; CI: 0.948-1.000; p=0.05) and for each 1% {Delta}StrTIL increment, the risk of distant metastases was reduced by 4.3% (hazard ratio: 0.957; CI: 0.932-0.983; p=0.001). The prognostic role of StrTIL in HR positive cases could not be proven.\n\nConclusionsStrTIL expression might be stimulated by highly (platinum), moderately (cyclophosphamide) and marginally (taxane, anthracycline) mutagenic chemotherapeutic agents. Increase in StrTIL in residual cancer compared to pre-treatment tumor tissue is associated with improved distant metastasis-free survival in cases with HR negative breast carcinoma.

cancer biology↗

bioRxiv2018

Strand Orientation Bias Detector (SOBDetector) to remove artifacts from sequencing data of formalin fixed samples

Formalin-fixed paraffin-embedded (FFPE) tissue, the most common tissue specimen stored in clinical practice, presents challenges in the analysis due to formalin-induced artifacts. Here we present SOBDetector, that is designed to remove these artifacts from a list of variants, which were extracted from next-generation sequencing data, using the posterior predictive distribution of a Bayesian logistic regression model trained on TCGA whole exomes. Based on a concordance analysis, SOBDetector outperforms the currently publicly available FFPE-filtration techniques (Accuracy: 0.9 {+/-} 0.015, AUC = 0.96). SOBDetector is implemented in Java 1.8 and is freely available online.

bioinformatics↗

bioRxiv2018

Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors

Due to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.\n\nKey messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the \"my choice\" HRD score in collaboration with Myriad Genetics.\n\nThese confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.

cancer biology↗