Biology subjects

Hausler, R.

Publications and source records attributed to Hausler, R..

8 recordsLinked to original sources

bioRxiv2025

Gastric epithelium from BRCA1 and BRCA2 carriers harbors increased double-stranded DNA damage and augmented growth.

An accumulating body of evidence suggests carriers of a pathogenic germline variant (PGV) in BRCA1 or BRCA2 have increased gastric cancer (GC) risk. BRCA1 and BRCA2 are tumor suppressor genes involved in promoting homologous recombination to repair double-stranded DNA breaks. The aim of this investigation was to identify differences within the gastric epithelium and in patient-derived gastric organoids (PDGOs) between BRCA1 and BRCA2 carriers and non-carriers to determine if evidence of early gastric carcinogenesis exists amongst these carriers. First, using gastric epithelial biopsies, BRCA2 carriers were found to harbor higher expression of the proliferative marker Ki-67 within the antral gastric epithelium and strikingly, biopsies from both BRCA1 and BRCA2 carriers displayed a marked increase in double-stranded DNA damage. These results were further explored using PDGOs, where a growth advantage was observed for both BRCA1 and BRCA2 PDGOs compared to non-carrier PDGOs. Furthermore, both BRCA1 and BRCA2 PDGOs displayed a more pronounced enhancement of Ki-67 expression as well as increased double stranded DNA damage compared to non-carrier PDGOs. Importantly, none of the PDGOs showed signs of BRCA1 or BRCA2 loss of heterozygosity, potentially indicating a haploinsufficient phenotype. Taken together, these novel findings suggest that haploinsufficiency in BRCA1 and BRCA2 carriers may lead to DNA damage in the gastric epithelium, which may serve as an early event contributing to GC development.

cancer biology↗

bioRxiv2025

Variation at the R181 residue of p53 confers loss of p53 DNA binding cooperativity with the retention of mitochondrial-associated apoptosis

The p53 tumor suppressor binds DNA cooperatively as a tetramer, mediated by salt-bridge interactions between p53 residues E180 and R181. Variants at the R181 residue are one of the most identified TP53 pathogenic variants by germline genetic testing. We show that families with TP53 p.R181H and p.R181C variants have an attenuated cancer risk phenotype compared to patients with hotspot dominant negative loss of function TP53 variants. Despite this phenotype, we find that p53 R181H and R181C variants have significantly reduced ability to bind to p53 promoter/enhancer target sequences and transactivate p53 target genes, similar to null variants. However, p53 R181H and R181C retain wild-type p53 structure and tetramerization. In addition, R181-mutant cells undergo apoptosis through wild-type p53 activity at the mitochondria. These results indicate that retention of transcription-independent p53 tumor suppressor function results in a reduced penetrance cancer risk syndrome in humans. Statement of SignificanceInherited TP53 variants cause Li-Fraumeni Syndrome (LFS), which has significant phenotypic heterogeneity in lifetime cancer risk. Our study shows that retention of transcription-independent p53 functions, despite loss of p53 transactivation activity, results in a reduced penetrance phenotype. Classification of TP53 variants should incorporate assays of transcriptional and non-transcriptional functions.

cancer biology↗

bioRxiv2024

Oncogenic Alterations, Race, and Survival in US Veterans with Metastatic Prostate Cancer Undergoing Somatic Tumor Next Generation Sequencing

PurposeNational guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans. Patients and MethodsThis retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival. Results5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in SPOP (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including TP53 were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]). ConclusionIn the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.

genomics↗

bioRxiv2024

Chemoresistance of TP53 mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene, TP53 (TP53mut AML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples show TP53mut AML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit in TP53mut AML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically, TP53mut AML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizes TP53mut AML cell lines and primary samples in vitro and in vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target in TP53mut AML. SignificanceChemotherapy-persisting TP53mut AML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.

cancer biology↗

bioRxiv2024

Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Pathogenic germline TP53 alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of TP53 with no recurrent oncogenic variants except ERBB2 (HER2) amplification. Compared to sporadic BC, in situ and invasive LFS-BC exhibited a high burden of short amplified aneuploid segments (SAAS). Pro-apoptotic p53 target genes BAX and TP53I3 failed to be up-regulated in LFS-BC as was seen in sporadic BC compared to normal breast tissue. LFS-BC had lower CD8+ T-cell infiltration compared to sporadic BC yet higher levels of proliferating cytotoxic T-cells. Within LFS-BC, progression from in situ to invasive BC was marked by an increase in chromosomal instability with a decrease in proliferating cytotoxic T-cells. Our study uncovers critical events in mutant p53-driven tumorigenesis in breast tissue.

genetics↗

bioRxiv2023

UV reflectance in crop remote sensing: Assessing the current state of knowledge and extending research with strawberry cultivars.

Remote sensing of spectral reflectance is a crucial parameter in precision agriculture. In particular, the visual color produced from reflected light can be used to determine plant health (VIS-IR) or attract pollinators (Near-UV). However, the UV spectral reflectance studies largely focus on non-crop plants, even though they provide essential information for plant-pollinator interactions. This literature review presents an overview of UV-reflectance in crops, identifies gaps in the literature, and contributes new data based on strawberry cultivars. The study found that most crop spectral reflectance studies relied on lab-based methodologies and examined a wide spectral range (Near UV to IR). Moreover, the plant family distribution largely mirrored global food market trends. Through a spectral comparison of white flowering strawberry cultivars, this study discovered visual differences for pollinators in the Near UV and Blue ranges. The variation in pollinator visibility within strawberry cultivars underscores the importance of considering UV spectral reflectance when developing new crop breeding lines and managing pollinator preferences in agricultural fields.

plant biology↗

bioRxiv2022

HRDex: a tool for deriving homologous recombination deficiency (HRD) scores from whole exome sequencing data

BackgroundBreast and ovarian tumors in patients with biallelic BRCA1 and BRCA2 mutations either by germline mutations accompanied by allele-specific loss of heterozygosity (LOH) or truncal somatic mutations respond to PARP inhibition. The repair of double stranded DNA breaks in tumors these tumors leads to homologous recombination deficiency (HRD), which can be measured using a variety of genomic and transcriptomic signatures. However, the optimal biomarker for BRCA deficiency is unknown. MethodsWe developed HRDex to determine HRD and its composite scores from allele specific copy number data analysis of whole exome sequencing (WES) data and examined the discriminatory ability of HRDex and other genomic and transcriptomic measures to identify BRCA deficiency in breast and ovarian tumors from The Cancer Genome Atlas (TCGA). ResultsHRDex scores have high correlation with SNP array based HRD scores in both breast and ovarian cancers. HRDex scores have high discriminatory accuracy to distinguish BRCA deficient breast tumors, similar to SNP array based scores (AUC 0.87 vs 0.90); however, discriminatory ability for ovarian tumors was lower (AUC 0.79 vs 0.90). HRD-LST had the best discriminatory ability of the three composite HRD scores. HRDex had higher discriminatory ability for identification of BRCA deficiency than RNA expression based scores (eCARD, tp53, RPS and PARPi7) in breast and ovarian tumors. Tumor mutational burden (TMB) was associated with BRCA deficiency in breast but not ovarian cancer. Combining HRDex score with mutational signature 3 modestly increased discriminatory ability for BRCA deficient breast and ovarian tumors (breast: AUC 0.90 vs 0.87; ovarian: AUC 0.83 vs 0.79). ConclusionsWES based HRD scores perform similarly to SNP array HRD scores, and better than other genomic or transcriptomic signatures, for identification of tumors with BRCA deficiency due to biallelic BRCA loss.

genomics↗

bioRxiv2018

DataRemix: a universal data transformation for optimal inference from gene expression datasets

MotivationRNAseq technology provides unprecedented power in the assesment of the transcription abundance and can be used to perform a variety of downstream tasks such as inference of gene-correlation network and eQTL discovery. However, raw gene expression values have to be normalized for nuisance biological variation and technical covariates, and different normalization strategies can lead to dramatically different results in the downstream study. ResultsWe describe a generalization of SVD-based reconstruction for which the common techniques of whitening, rank-k approximation, and removing the top k principle components are special cases. Our simple three-parameter transformation, DataRemix, can be tuned to reweight the contribution of hidden factors and reveal otherwise hidden biological signals. In particular, we demonstrate that the method can effectively prioritize biological signals over noise without leveraging external dataset-specific knowledge, and can outperform normalization methods that make explicit use of known technical factors. We also show that DataRemix can be efficiently optimized via Thompson Sampling approach, which makes it feasible for computationally expensive objectives such as eQTL analysis. Finally we reanalyze the Depression Gene Networks (DGN) dataset, and we highlight new trans-eQTL networks which were not reported in the initial study. AvailabilityDataRemix is an R package which is freely available at GitHub (https://github.com/wgmao/DataRemix). Contactmchikina@pitt.edu

genomics↗