About

Katherine L. Nathanson, MD, is the Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania. She is a member of multiple research centers including the Center for Research on Reproduction and Women's Health, the Center of Excellence in Environmental Toxicology, and the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania. Dr. Nathanson serves as the Director of Genetics at the Basser Research Center and is the Deputy Director of the Abramson Cancer Center. Her research expertise focuses on hereditary breast and ovarian cancer, with her group investigating the variable risks associated with different mutation types and locations in BRCA1 and BRCA2, as well as the distribution of these mutations worldwide. She has contributed to understanding tumor heterogeneity, immunogenicity in BRCA mutation-associated cancers, and the genetic basis of testicular germ cell tumors, among other areas. Her work includes identifying novel susceptibility genes, characterizing tumor genetics, and elucidating mechanisms of resistance and response to cancer therapies.

Research topics

• Biology
• Genetics
• Medicine
• Oncology
• Computer Science
• Computational biology
• Environmental health
• Internal medicine
• Political Science
• Bioinformatics
• Statistics
• Obstetrics
• Data science
• Cancer research
• Database
• Gynecology

Selected publications

• Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer.

  Apollo (University of Cambridge) · 2026-01-09

  article

  The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

  Publisher

• Landscape of reversion alterations in homologous recombination genes reveals evolutionary constraints

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-21

  articleOpen accessSenior author

  Reversion mutations (REVs) restore homologous recombination repair (HRR) and confer resistance to PARP inhibitors (PARPi) in HR-deficient cancers. Yet, their prevalence, mechanisms, and biological constraints remain undefined. We analyzed genomic profiling of 609,464 tissue and liquid biopsy samples across multiple cancer types to delineate the pan-cancer landscape of REVs. REVs were identified in eight HRR genes, most frequently BRCA2 and BRCA1 and notably never in ATM or CHEK2. REVs exclusively impacted truncating pathogenic variants, predominantly through large in-frame and exon-level deletions, associated with repetitive sequences. Conserved functional domains are relatively depleted of REVs. Structural modeling and functional studies support that exon-level deletions preserve critical domain architecture and confer PARPi resistance. The study establishes HRR reversion as a structurally permissive, yet evolutionarily constrained, resistance mechanism with implications on response, monitoring, and therapeutic strategy.

  PublisherDOI

• Figure S5 from <i>NBN</i> Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and <i>In Vitro</i> DNA Damage Response Defects

  2025-11-25

  articleOpen access

  <p>Supplementary Figure S5. Cancer types diagnosed in the carriers of germline NBN variants found to be enriched in cases compared to controls. Information about somatic loss of heterozygosity (LOH) is included. NSCLC: NonSmall Cell Lung Cancer, CUP, Cancer of Unknown Primary.</p>

  PublisherOA PDFDOI

• Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

  The Breast · 2025-10-30 · 1 citations

  articleOpen access

  The breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates.

  PublisherDOI

• Supplementary Tables S1-S11 from <i>NBN</i> Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and <i>In Vitro</i> DNA Damage Response Defects

  2025-11-25

  articleOpen access

  <p>Excel file with all the supplementary tables (S1-S11) in separate tabs</p>

  PublisherDOI

• Figure S7 from <i>NBN</i> Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and <i>In Vitro</i> DNA Damage Response Defects

  2025-11-25

  articleOpen access

  <p>Supplementary Figure S7. NBN Multi-species protein alignment.</p>

  PublisherOA PDFDOI

• CCR5 blockade: A therapeutic approach to uncouple CART-BCMA expansion from CART-mediated immune toxicities.

  Blood · 2025-11-03 · 2 citations

  articleOpen access

  Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapy is standard care for relapsed or refractory hematologic malignancies. As clinical use expands, rare but serious toxicities beyond cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are emerging. These include hyperleukocytosis and, specifically, following BCMA-directed CART (CART-BCMA) therapy, delayed neurotoxicity and enterocolitis. We named these post–CART-BCMA complications, distinct from CRS and ICANS, as CART immune-related adverse events (CirAE). CirAE are associated with elevated CART expansion in the first two weeks, suggesting that modulating CART-BCMA proliferation without affecting CART effector function could improve safety and expand therapeutic use. Method: We retrospectively analyzed a cohort of 198 multiple myeloma (MM) patients treated with CART-BCMA (idecabtagene vicleucel [ide-cel] and ciltacabtagene autoleucel [cilta-cel]) at the University of Pennsylvania (June 2021-December 2024) to identify predictors of CirAE and to investigate the mechanisms underlying the early onset of CirAE. Serial serum samples were analyzed using 32-plex proteomics (Luminex). Immune cell subsets were characterized serially by multiparametric flow cytometry. T-cell proliferation was assessed using CellTrace Violet. Cytotoxic CART function was evaluated via luciferase assays. Results: In this large cohort, both peak absolute lymphocyte count (ALC) ≥ 2.4 × 10³/μL and CD4:CD8 ratio >1 at apheresis independently predicted CirAE following CART-BCMA. To investigate mechanisms underlying elevated ALC, we analyzed a unique case (Cilta#1) marked by extreme, polyclonal CART expansion and three distinct post-infusion CirAE: facial palsy, delayed ICANS, and severe enterocolitis. Cilta#1 exhibited hyperleukocytosis (peak ALC: 197.5 × 10³/μL, Day 13) and profound CD4-skewed CART expansion (CD4:CD8 ratio: 12.6). Despite the magnitude, the CART population remained polyclonal, as confirmed by TCR Vβ sequencing and vector integration site analysis (>20,000 unique sites). Whole-exome sequencing of blood and marrow excluded clonal transformation or pathogenic mutations. Longitudinal flow cytometry from pre-lymphodepletion to month 15 showed persistent CD4 skewing, with CART displaying a highly activated, proliferative phenotype(HLA-DR+/Ki-67+). Serum proteomics at day 7, prior to peak expansion, revealed elevated lymphoproliferative cytokines (IL-2, IL-7, IL-15) and chemokines (CCL5, CXCL9, CXCL10). Given these findings, we assessed the dominant proliferative signal via cytokine-stimulated proliferation assays on Cilta#1 CART cells. IL-15 elicited the strongest proliferation and pSTAT5 activation. In vitro, IL-15 induced CCL5 secretion in both Cilta#1 and healthy donor CART (n=3); however, only Cilta#1 cells upregulated CCR5, a pattern absent in donor CART, where CCR5 was actually downregulated after cytokine exposure. These results suggest a potential IL-15–driven CCL5–CCR5 loop sustaining CART expansion in Cilta#1. We hypothesized that this axis contributes to the elevated ALC observed in patients with CirAE. To test this, we cultured healthy donor CART + 25% Cilta#1 day 7 serum, and observed significantly enhanced survival compared to serum from three other cilta-cel patients (p < 0.001). This effect was abrogated by 40 μM maraviroc,an FDA approved CCR5 antagonist, highlighting the key role of CCR5 signaling. Notably, maraviroc suppressed both IL-15–induced and antigen-dependent CART proliferation across multiple donors (n=4), suggesting broader applicability. Importantly, maraviroc did not impair CART viability or anti-myeloma cytotoxicity, as assessed by flow cytometry for CD107a, granzyme B, and MM.1S tumor killing. CCR5 blockade (20 µg/mL) inhibited IL-15–induced proliferation in Cilta#1 CART, further validating CCR5 as a key effector node. Finally, CCR5 knockout impaired antigen-driven proliferation and rendered CART insensitive to maraviroc, confirming on-target specificity.Conclusion: We identified the IL-15–CCL5–CCR5 circuit as a key driver of CART-BCMA proliferation in CirAE and demonstrated that CCR5 blockade safely restrains CART-BCMA expansion while preserving their anti-myeloma activity. These findings support CCR5-directed targeted strategies to selectively modulate CART expansion without compromising efficacy.

  PublisherOA PDFDOI

• G4mer: An RNA language model for transcriptome-wide identification of G-quadruplexes and disease variants from population-scale genetic data

  Nature Communications · 2025-11-20

  articleOpen access

  Abstract RNA G-quadruplexes (rG4s) are key regulatory elements in gene expression, yet the effects of genetic variants on rG4 formation remain underexplored. Here, we introduce G4mer, an RNA language model that predicts rG4 formation, classifies rG4 subtypes, and evaluates the effects of genetic variants across the transcriptome. G4mer significantly improves accuracy over existing methods and uncovers subtype-specific differences in mutational sensitivity and evolutionary constraint, highlighting sequence length and flanking motifs as important rG4 features. Applying G4mer to $${5}^{{\prime} }$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msup> <mml:mrow> <mml:mn>5</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>′</mml:mo> </mml:mrow> </mml:msup> </mml:math> untranslated region (UTR) variations, we identify variants in breast cancer-associated genes that alter rG4 formation and validate their impact on structure and gene expression. These results demonstrate the potential of integrating computational models with experimental approaches to study rG4 function, especially in diseases where non-coding variants are often overlooked. To support broader applications, G4mer is available as both a web tool and a downloadable model.

  PublisherOA PDFDOI

• Supplementary Materials, Figure S1-S4, Table S1-S9 from Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C

  2025-11-24

  articleOpen access

  &lt;p&gt;Supplementary Materials, References, Tables and Figures&lt;/p&gt;

  PublisherDOI

• Figure S3 from &lt;i&gt;NBN&lt;/i&gt; Pathogenic Germline Variants are Associated with Pan-Cancer Susceptibility and &lt;i&gt;In Vitro&lt;/i&gt; DNA Damage Response Defects

  2025-11-25

  articleOpen access

  &lt;p&gt;Supplementary Figure S3. Rates of somatic loss of heterozygosity (LOH) stratified by cancer type. NSCLC: NonSmall Cell Lung Cancer, CRC: Colorectal Cancer.&lt;/p&gt;

  PublisherOA PDFDOI

Recent grants

• Radiation and checkpoint blockade for cancer immune therapy

  NIH · $18.3M · 2017–2024

• Post genome wide association studies in testicular germ cell tumors

  NIH · $11.7M · 2012–2026

• Postdoctoral Training Program in Genomic Medicine

  NIH · $3.7M · 2017–2027

• Identifying and validating novel susceptibility genes for breast cancer

  NIH · $3.4M · 2014–2019

• NIH Grant R01CA135509

  NIH · $2.3M · 2014

Frequent coauthors

• Susan M. Domchek

  University of Pennsylvania

  1012 shared

• Fergus J. Couch

  Mayo Clinic in Arizona

  763 shared

• Esther M. John

  Public Health Ontario

  483 shared

• Paolo Radice

  477 shared

• Olufunmilayo I. Olopade

  421 shared

• Christian F. Singer

  Comprehensive Cancer Center Vienna

  413 shared

• Irene L. Andrulis

  Lunenfeld-Tanenbaum Research Institute

  406 shared

• Susan L. Neuhausen

  398 shared

Awards & honors

• Pearl Basser Professor for BRCA-Related Research at the Abra…