Biology subjects

Maxwell, K. N.

Publications and source records attributed to Maxwell, K. N..

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↗

bioRxiv2024

Homologous recombination deficiency and tumor suppressor heterozygosity mediate resistance to front-line therapy in breast cancer

The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g)BRCA2-associated tumors are enriched for RB1 loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations. Amongst these tumors, gBRCA2-related homologous recombination deficiency (HRD) as well as baseline RB1 LOH status promote acquisition of RB1 loss-of- function mutations under the selective pressure of CDK4/6i, causing therapy resistance. These findings suggest an alternative therapeutic strategy using sequential targeting of HRD in gBRCA- associated breast cancers through PARP inhibitors prior to CDK4/6i therapy to intercept deleterious RB1-loss trajectories and thus suppress the emergence of CDK4/6 inhibitor resistance. More broadly, our findings demonstrate how germline-somatic driven genomic configurations shape response to systemic therapy and can be exploited therapeutically as part of biomarker-directed clinical strategies.

genomics↗

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↗

bioRxiv2019

Assessing a causal relationship between circulating lipids and breast cancer risk via Mendelian randomization

ObjectiveTo assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.\n\nDesignMendelian randomization (MR) study.\n\nSetting and ParticipantsData from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.\n\nExposuresGenetically modified plasma levels of LDL, HDL, or TG.\n\nMain Outcomes and MeasuresOdds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.\n\nResultsWe observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4x10-5).\n\nMultivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9x10-4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06-1.16, P=1.5x10-6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.\n\nConclusionsGenetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.

genomics↗