Biology subjects

Neuhausen, S. L.

Publications and source records attributed to Neuhausen, S. L..

11 recordsLinked to original sources

bioRxiv2026

Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous disease with limited targeted treatment options. Leveraging bulk and spatial transcriptomics and cellular mapping of breast tissue from a large patient cohort, we identified three reproducible TNBC ecosystem subtypes that encode distinct spatial tumor-microenvironment architectures and clinically relevant treatment-response phenotype. Our analyses define: (1) an immune-exhausted subtype associated with immune checkpoint therapy (ICT); (2) a highly fibrotic/hypoxic subtype; and (3) a metabolically reprogrammed subtype characterized by nuclear-receptor and fatty-acid signaling. Spatial profiling further revealed subtype-specific organization of epithelial, immune, and stromal programs across tumor centers and invasive edges. Multiplexed imaging independently supported the contrasting immune-infiltrated and stromal-excluded architectures of the immune-engaged and fibrotic subtypes. The unique markers associated with the subtypes also provide the basis for subtyping and candidate therapeutic vulnerabilities. Our study provides a robust framework for personalized medicine, highlighting that targeting specific spatio-cellular architectures is critical to improving clinical outcomes.

cancer biology↗

bioRxiv2025

Shared TCRs in peripheral blood offer robust celiac disease classification independent of gluten Intake

Background and AimsCeliac disease (CeD) is a chronic digestive autoimmune disorder affecting approximately 1% of the worldwide population. It is driven by T cells activated by specific HLA-DQ2 or HLA-DQ8 molecules leading to the destruction of intestinal villi. We aimed to characterize shared CeD-specific T cells in patients on and off a gluten-free diet (GFD) from a large cohort of cases and controls. MethodsWe performed bulk TCR{beta} immune sequencing of the peripheral blood of 1,604 biopsy-confirmed CeD patients (1,339 on GFD, 265 on normal diet) and 1,100 controls. We identified over 300 TCR{beta}s enriched in CeD cases versus controls in an HLA-aware manner, controlling for CeD risk alleles. ResultsCeD-associated TCR{beta}s were found to be more predictive of disease than previously characterized gliadin and glutenin-binding TCRs in a validation cohort. Furthermore, the clonal breadth of these TCR{beta}s was associated with increased intestinal damage. Immune sequencing of the peripheral blood also uncovered repertoire-level differences between CeD patients and controls. CeD patients displayed significantly higher productive clonality compared to age-matched controls as well as expansion of TCR{beta}s specific to cytomegalovirus (CMV) and Epstein-Barr Virus (EBV). ConclusionsThese findings underscore the value of unbiased immune repertoire sequencing to identify novel biomarkers for autoimmune disease and to discover new disease mechanisms which can improve both diagnosis and treatment of disease.

immunology↗

bioRxiv2025

A novel subtyping method for TNBC with implications for prognosis and therapy

The biological heterogeneity of triple-negative breast cancer (TNBC) poses significant challenges for diagnosis, prognosis, and treatment. While prior TNBC subtype classifications exist, they are not widely used clinically. Here, we aimed to subtype TNBC based on transcriptomic profiles using cell type and state heterogeneity in tumor tissue from 250 pre-treatment women (127 African-American and 123 European-American). We identified three major subtypes and three distinct groups exhibiting unique cell-type composition and mechanisms: Subtype-1 immune signaling/T-cell response; Subtype-2 pro-fibrotic and immune desert; Subtype-3 fatty acid and nuclear receptor signaling. Subtype-1 showed potential responsiveness to immunotherapy, while Subtypes-2 and 3 suggested alternative therapeutic targets. In Subtype-3, which contained a patient group with high ESR1, (but not high ER protein expression) we identified putative mutations in the gene that are unique to these patients. This framework provides a path toward personalized TNBC treatment and is accessible through a user-friendly RShiny application for clinical use.

bioinformatics↗

bioRxiv2022

Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

Effects from aging in single cells are unpredictable, whereas aging phenotypes at the organ- and tissue-levels tend to appear as stereotypical changes. The mammary epithelium is a bilayer of two major phenotypically and functionally distinct cell lineages, the luminal epithelial and myoepithelial cells. Mammary epithelia exhibit substantial stereotypical changes with age that merits attention because they are putative breast cancer-cells-of-origin. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increases susceptibility to cancer initiation. We identified two models of age-dependent changes in gene expression, directional changes and increased variance, which contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and implicated downregulation of chromatin and genome organizers such as SATB1. Epithelial expression of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal detectable in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminal-specific aging distinguished normal from cancer tissue and was predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the variant responses to aging in their surrounding tissue and that their emergent aging phenotype both endows cells with the ability to become cancer-cells-of-origin and embodies a biosensor that presages cancer susceptibility.

cancer biology↗

bioRxiv2022

Profile of the somatic mutational landscape in breast tumors from Hispanic/Latina women

Breast cancer causes the most cancer deaths among Hispanic/Latinas (H/L). However, limited tumor-sequencing data from H/L are available to guide treatment. To address this gap, we performed whole-exome sequencing of DNA from 140 HL germline and 146 matched breast tumors and RNA-seq for the tumors. We generated somatic-mutation profiles, identified copy-number alterations (CNAs), and compared results to non-Hispanic White (White) women in The Cancer Genome Atlas. Similar to Whites, PIK3CA and TP53 were the most commonly mutated genes in breast tumors from H/L. We found 4 common COSMIC mutation signatures (1, 2, 3, 13) and signature 16 not previously reported in other breast-cancer datasets. We observed recurrent amplifications in breast-cancer drivers including MYC, FGFR1, CCND1, and ERBB2, and a recurrent amplification on 17q11.2 associated with high KIAA0100 gene expression, implicated in breast-cancer aggressiveness. Expanded research is required to determine how these characteristics of H/L tumors impact treatment response and survival.

cancer biology↗

bioRxiv2022

Variable Number Tandem Repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of BRCA1 185delAG, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, and tested the association of VNTRs and breast cancer risk using Cox regression models. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at development of breast cancer in carriers of the risk genotypes compared to those without the risk genotypes for seven of eight VNTRs. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for disease and have larger effects than SNPs.

cancer biology↗

bioRxiv2021

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

Aging causes molecular changes that manifest as stereotypical phenotypes yet aging-associated diseases progress only in certain individuals. At lineage-specific resolution, we show how stereotyped and variant responses are integrated in mammary epithelia. Age-dependent directional changes in gene expression and DNA methylation (DNAm) occurred almost exclusively in luminal cells and implicated genome organizers SATB1 and CTCF. DNAm changes were robust indicators of aging luminal cells, and were either directly (anti-)correlated with expression changes or served as priming events for subsequent dysregulation, such as demethylation of ESR1-binding regions in DNAm-regulatory CXXC5 in older luminal cells and luminal-subtype cancers. Variance-driven changes in the transcriptome of both luminal and myoepithelial lineages further contributed to age-dependent loss of lineage fidelity. The pathways affected by transcriptomic and DNAm changes during aging are commonly linked with breast cancer, and together with the differential variability found across individuals, influence aging-associated cancer susceptibility in a subtype-specific manner.

cancer biology↗

bioRxiv2020

Variable Number Tandem Repeats mediate the expression of proximal genes

Variable Number Tandem Repeats (VNTRs) account for a significant amount of human genetic variation. VNTRs have been implicated in both Mendelian and Complex disorders, but are largely ignored by whole genome analysis pipelines due to the complexity of genotyping and the computational expense. We describe adVNTR-NN, a method that uses shallow neural networks for fast read recruitment. On 55X whole genome data, adVNTR-NN genotyped each VNTR in less than 18 cpu-seconds, while maintaining 100% accuracy on 76% of VNTRs. We used adVNTR-NN to genotype 10,264 VNTRs in 652 individuals from the GTEx project and associated VNTR length with gene expression in 46 tissues. We identified 163 eVNTR loci that were significantly associated with gene expression. Of the 22 eVNTRs in blood where independent data was available, 21 (95%) were replicated in terms of significance and direction of association. 49% of the eVNTR loci showed a strong and likely causal impact on the expression of genes and 80% had maximum effect size at least 0.3. The impacted genes have important role in complex phenotypes including Alzheimers, obesity and familial cancers. Our results point to the importance of studying VNTRs for understanding the genetic basis of complex diseases.

genomics↗

bioRxiv2019

Evaluation of ACMG Rules for In silico Evidence Strength Using An Independent Computational Tool Absent of Circularities on ATM and CHEK2 Breast Cancer Cases and Controls

The American College of Medical Genetics and Genomics (ACMG) guidelines for sequence variant classification include two criteria, PP3 and BP4, for combining computational data with other evidence types contributing to sequence variant classification. PP3 and BP4 assert that computational modeling can provide \"Supporting\" evidence for or against pathogenicity within the ACMG framework. Here, leveraging a meta-analysis of ATM and CHEK2 breast cancer case-control mutation screening data, we evaluate the strength of evidence determined from the relatively simple computational tool Align-GVGD. Importantly, application of Align-GVGD to these ATM and CHEK2 data is free of logical circularities, hidden multiple testing, and use of other ACMG evidence types. For both genes, rare missense substitutions that are assigned the most severe Align-GVGD grade exceed a \"Moderate pathogenic\" evidence threshold when analyzed in a Bayesian framework; accordingly, we argue that the ACMG classification rules be updated for well-calibrated computational tools. Additionally, congruent with previous analyses of ATM and CHEK2 case-control mutation screening data, we find that both genes have a considerable burden of pathogenic missense substitutions, and that severe ATM rare missense have increased odds ratios compared to truncating and splice junction variants, indicative of a potential dominant-negative effect for those missense substitutions.

genetics↗

bioRxiv2019

Epithelial ovarian cancer and schizophrenia and schizophrenia on circulating glycerophosphocholine metabolites: a Mendelian randomization study

Most women with epithelial ovarian cancer (EOC) present with late-stage disease. As a result, globally, EOC is responsible for more than 150,000 deaths a year. Thus, a better understanding of risk factors for developing EOC is crucial for earlier screening and detection to improve survival. To that effort, there have been suggestions that there is an association of schizophrenia and cancer, possibly because metabolic changes are a hallmark of both cancer and schizophrenia (SZ). Perturbed choline metabolism has been documented in both diseases. Our objective was to use Mendelian randomization to evaluate whether SZ increased risk for developing EOC or the converse, and, whether SZ impacted glycerophosphocholine (GPC) metabolites. We found that SZ conferred a weak but increased risk for EOC, but not the reverse (no evidence that EOC caused SZ). SZ was also causally associated with lower levels of two GPC species and with suggestively lower levels in an additional three GPCs. We postulate that perturbed choline metabolism in SZ may mimic or contribute to a \"cholinic\" phenotype, as observed in EOC cells.

genetics↗

bioRxiv2019

A polygenic risk score for breast cancer in U.S. Latinas and Latin-American women

BackgroundOver 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Since most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry.\n\nMethodsWe conducted a pooled case-control analysis of U.S. Latinas and Latin-American women (4,658 cases, 7,622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (p < 5 x 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression and assessed discrimination using area under the receiver operating characteristic curve (AUROC). We also assessed PRS performance across quartiles of Indigenous American genetic ancestry.\n\nResultsOf 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally significant (p < 0.05). The PRS was associated with breast cancer risk, with an odds ratio (OR) per standard deviation increment of 1.58 (95% CI 1.52 to 1.64) and AUCROC of 0.63 (95% CI 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry.\n\nConclusionsThe 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

epidemiology↗