Katherine L. Nathanson, MD

faculty photo
Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania
Member, Abramson Cancer Center, University of Pennsylvania
Member, Center for Research on Reproduction and Women's Health, University of Pennsylvania
Member, Center of Excellence in Environmental Toxicology, University of Pennsylvania
Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania
Director of Genetics, Basser Research Center, Perelman School of Medicine at the University of Pennsylvania
Deputy Director, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania
Program Director, Combined Internal Medicine - Clinical Genetics Residency, University of Pennsylvania
Co-Chair, Limited Application Selection Committee, Perelman School of Medicine at the University of Pennsylvania
Department: Medicine

Contact information
421 Curie Blvd
University of Pennsylvania
Philadelphia, PA 19104
Office: 215-662-4740
B.A. (Biology)
Haverford College, Haverford, PA, 1987.
University of Pennsylvania School of Medicine, Philadelphia, PA, 1993.
Permanent link
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Description of Research Expertise

Hereditary Breast Cancer
The research in the Nathanson Group in hereditary breast and ovarian cancer started when I was post-doctoral fellow, training under Dr. Barbara Weber. Most recently, we have published studies demonstrating variable risks of breast and ovarian cancers with differing mutation types and locations with BRCA1 and BRCA2 (JAMA, 2015), and described the world-wide distribution of mutations (Hum Mutat, 2018). My group has evaluated the rate of moderate risk gene mutations in early onset breast cancer (Genet Med, 2015; NPJ Breast Cancer ,2017), contributed to consensus statements on the risk of these mutations (NEJM, 2015; Nat Rev Clinic Oncol, 2016), and evaluated the use of the ACMG guidelines for variant annotation of these genes (Am J Hum Genet, 2016). We published a somatic characterization of tumors associated with BRCA1/2 germline mutations and demonstrated that a significant proportion do not have allele-specific loss of heterozygosity, associated with differential genetic/genomic characteristics and survival after treatment (Nat Comm, 2017). We have preliminary data following up.

Example Projects:

1) Identification of novel breast cancer susceptibility genes using large scale sequencing in high risk and case-control cohort studies
2) Characterization of moderate penetrance breast cancer susceptibility genes in large cohorts
3) Characterization of immunogenicity in BRCA1/2 mutation associated cancers, understanding the associated molecular features and role of aneuploidy (working with cancer immunologists at Penn Medicine)
4) Understanding tumor heterogeneity in BRCA1/2 mutation associated cancers, by using single cell sequencing, high-depth targeted sequencing and large scale
5) Working with Dr. E. John Wherry’s group to elucidate immune function in healthy BRCA1/2 mutation carriers

Our research efforts in melanoma have spanned the past decade. Over this time period, we have worked with Dr. Meenhard Herlyn’s group at the Wistar Institute to lead efforts on the genetic and genomic characterization of cell lines and PDX used in pre-clinical modeling in melanoma, working, leading to over 25 publications focusing on intrinsic and acquired resistance to multiple different types of therapies. This effort cumulated in the publication of targeted massively parallel sequencing to characterize over 450 tumors, cell lines and patient derived xenografts (PDX) (Cell Reports, 2017). In the past, we also have worked on correlative studies in conjunction with clinical trials. We have two funded projects investigating inherited variation in association with outcome and immune related adverse events after treatment with checkpoint blockade, which are coming to fruition. Building upon our experience in massively parallel sequencing, the project we are doing on inherited variation in association with response to ipilimumab and our location within the Institute for Immunology, in the past two years, we also have worked on interdisciplinary projects that involve both cancer genetics and cancer immunology, specifically in melanoma (Nature, 2017; Nature Medicine, 2019), and have a funded core for massively parallel sequencing and analysis for the P01 Radiation – Immuno-oncology P01.

Example Projects:

1) Evaluating the intersection and function of non-canonical BRAF mutations with other MAPK mutations using single cell sequencing
2) Compilation of data on over 600 melanoma cell lines, PDX and tumor biopsies for in-depth analysis, with a particular view to determining if homologous recombination deficiency scores can be calculated from the targeted sequencing data (and correlate with mutation status)
3) Analysis of data on association of response and immune related adverse events after treatment with ipilimumab, focusing on specific pathways and HLA groups
4) Analysis of data on association of response and immune related adverse events after treatment with nivolumab and combination therapy (nivolumab and ipilimumab), focusing on specific pathways and HLA groups

Testicular Germ Cell Tumor
We identified the first (and only) validated candidate region associated with increased risk of TGCT in 2005 and went on to co-publish one of initial genome wide association studies (GWAS) study in TGCT (Nat Genet, 2009). GWAS in TGCT are the most successful in cancer, in terms of identifying loci with high effect sizes containing biologically plausible genes, which have implicated differences in male germ cell maturation and differentiation as being critical to disease susceptibility. We have subsequently published several other studies identifying loci associated with risk of TGCT. I currently lead the Testicular Cancer Association Consortium (TECAC), which is an international consortium of researchers (Nat Genet, 2009; Hum Mol Genet, 2011; Nat Genet, 2013; Hum Mol Genet, 2013; Hum Mol Genet, 2014; Nat Genet, 2017). These studies have furthered our understanding of the biology of TGCT as being a disease of male germ cell development, led to important genetic insights into the epidemiology of TGCT and identified the most significant loci (highest odds ratios) of any cancer GWAS. We also have generated whole exome data on several 100 patients with TGCT (JAMA Oncol, 2019), and plan more extensive sequencing, and have done ATAC-seq and Spatial-Seq (chromatin conformation capture) on multiple TGCT cell lines for post-GWA functional studies. We also heavily participated in the TCGA TGCT effort and have an ongoing collaborative project with multiple participants supported by Movember to evaluate resistance to Cisplatin in patients with TGCT.

Example Projects:

1) Identification of causal variants (SNPs) in regions associated with TGCT through in silico analysis, and subsequent functional/experimental evaluation
2) HiChIP (chromosome conformation capture using few input cells) in fetal and adult germ cells to define target-enhancer connectome and identify causal variants for TGCT
3) Whole genome sequencing of high-risk individuals with TGCT (bilateral, family history, non-white)
4) Follow-up from whole exome sequencing in case-control study to validate rare variants/genes in association with TGCT
5) Initiation and development of studies in non-whites with TGCT and women with ovarian germ tumors (also using social media)

Neuroendocrine Tumors
The Nathanson group works collaboratively with the Neuroendocrine Tumor Center at Penn Medicine on the genetics of pheochromocytoma and paraganglioma (PCC/PGL). They published their clinical genetic testing experience in PCC/PGL (Ann Surg Oncol, 2013), showing an inherited mutation rate of over 40%, accompanied by an editorial encouraging other clinicians to follow their paradigm for clinical genetic testing her group has established at Penn. Her group also was the first to identify somatic mutations in ATRX, associated with clinically aggressive disease (Nat Comm, 2015). Further, she co-led the Cancer Genome Atlas effort in PCC/PGL, which had multiple novel findings, including a recurrent fusion protein specific to this disease, and genetic/genomic predictors of poor prognosis (Cancer Cell, 2017). The group is continuing to collect samples from patients with PCC/PGL and SDHx mutations for further study.

Example Projects:

1) Evaluation of matched tumors – primary and recurrent PCC/PGL to identify mutations associated with metastatic disease
2) Evaluation of whole genome sequencing of PCC/PGL patients with no identified inherited mutations
3) Follow-up on studies suggesting that PCC/PGL with SDHx mutations have a BRCA-like phenotype, evaluating homologous recombination deficiency scores and PARP tracer up-take

Selected Publications

O'Mahony DG, Ramus SJ, Southey MC, Meagher NS, Hadjisavvas A, John EM, Hamann U, Imyanitov EN, Andrulis IL, Sharma P, Daly MB, Hake CR, Weitzel JN, Jakubowska A, Godwin AK, Arason A, Bane A, Simard J, Soucy P, Caligo MA, Mai PL, Claes KBM, Teixeira MR, Chung WK, Lazaro C, Hulick PJ, Toland AE, Pedersen IS; HEBON Investigators; Neuhausen SL, Vega A, de la Hoya M, Nevanlinna H, Dhawan M, Zampiga V, Danesi R, Varesco L, Gismondi V, Vellone VG, James PA, Janavicius R, Nikitina-Zake L, Nielsen FC, van Overeem Hansen T, Pejovic T, Borg A, Rantala J, Offit K, Montagna M, Nathanson KL, Domchek SM, Osorio A, García MJ, Karlan BY; GEMO Study Collaborators; De Fazio A, Bowtell D; AOCS Group; McGuffog L, Leslie G, Parsons MT, Dörk T, Speith LM, Dos Santos ES, da Costa AABA, Radice P, Peterlongo P, Papi L, Engel C, Hahnen E, Schmutzler RK, Wappenschmidt B, Easton DF, Tischkowitz M, Singer CF, Tan YY, Whittemore AS, Sieh W, Brenton JD, Yannoukakos D, Fostira F, Konstantopoulou I, Soukupova J, Vocka M; CZECANCA Consortium; Chenevix-Trench G, Pharoah PDP, Antoniou AC, Goldgar DE, Spurdle AB, Michailidou K; Consortium of Investigators of Modifiers of BRCA1/2; Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium: Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2. Br J Cancer 128(12): 2283-2294, Jun 2023.

Hu C, Belur Nagaraj A, Shimelis H, Montalban G, Lee KY, Huang H, Lumby CA, Na J, Susswein LR, Roberts ME, Marshall ML, Hiraki S, LaDuca H, Chao E, Yussuf A, Pesaran T, Neuhausen SL, Haiman CA, Kraft P, Lindström S, Palmer JR, Teras LR, Vachon CM, Yao S, Ong I, Nathanson KL, Weitzel JN, Boddicker N, Gnanaolivu R, Polley EC, Mer G, Cui G, Karam R, Richardson ME, Domchek SM, Yadav S, Hruska KS, Dolinsky J, Weroha SJ, Hart SN, Simard J, Masson JY, Pang YP, Couch FJ: Functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in RAD51C. Cancer Res May 2023 Notes: Online ahead of print.

Pyle LC, Kim J, Bradfield J, Damrauer SM, D'Andrea K, Einhorn LH, Godse R, Hakonarson H, Kanetsky PA, Kember RL, Jacobs LA, Maxwell KN, Rader DJ, Vaughn DJ, Weathers B, Wubbenhorst B, Regeneron Genetics Center Research Team, Cancer Genomics Research Laboratory, Greene MH, Nathanson KL, Stewart DR: Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes. Eur Urol Page: Online ahead of print, May 2023.

Lau-Min KS, McCarthy AM, Nathanson KL, Domchek SM: Nationwide Trends and Determinants of Germline BRCA1/2 Testing in Patients With Breast and Ovarian Cancer. J Natl Compr Canc Netw 21(4): 351-358, Apr 2023.

Yadav S, Boddicker NJ, Na J, Polley EC, Hu C, Hart SN, Gnanaolivu RD, Larson N, Holtegaard S, Huang H, Dunn CA, Teras LR, Patel AV, Lacey JV, Neuhausen SL, Martinez E, Haiman C, Chen F, Ruddy KJ, Olson JE, John EM, Kurian AW, Sandler DP, O'Brien KM, Taylor JA, Weinberg CR, Anton-Culver H, Ziogas A, Zirpoli G, Goldgar DE, Palmer JR, Domchek SM, Weitzel JN, Nathanson KL, Kraft P, Couch FJ: Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol 41(9): 1703-1713, Mar 2023.

Belhadj S, Khurram A, Bandlamudi C, Palou-Márquez G, Ravichandran V, Steinsnyder Z, Wildman T, Catchings A, Kemel Y, Mukherjee S, Fesko B, Arora K, Mehine M, Dandiker S, Izhar A, Petrini J, Domchek S, Nathanson KL, Brower J, Couch F, Stadler Z, Robson M, Walsh M, Vijai J, Berger M, Supek F, Karam R, Topka S, Offit K: NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects. Clin Cancer Res 29(2): 422-431, Jan 2023.

Maxwell KN, Patel V, Nead KT, Merrill S, Clark D, Jiang Q, Wubbenhorst B, D'Andrea K, Cohen RB, Domchek SM, Morrissette JJD, Greenberg RA, Babushok DV, Nathanson KL: Fanconi anemia caused by biallelic inactivation of BRCA2 can present with an atypical cancer phenotype in adulthood. Clin Genet 103(1): 119-124, Jan 2023.

Berna R, Mitra N, Hoffstad O, Wubbenhorst B, Nathanson KL, Margolis DJ: Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort. Arch Dermatol Res 314(10): 953-959, Dec 2022.

Lau-Min KS, McKenna D, Asher SB, Bardakjian T, Wollack C, Bleznuck J, Biros D, Anantharajah A, Clark DF, Condit C, Ebrahimzadeh JE, Long JM, Powers J, Raper A, Schoenbaum A, Feldman M, Steinfeld L, Tuteja S, VanZandbergen C, Domchek SM, Ritchie MD, Landgraf J, Chen J, Nathanson KL: Impact of integrating genomic data into the electronic health record on genetics care delivery. Genet Med 24(11): 2338-2350, Nov 2022.

Verma A, Damrauer SM, Naseer N, Weaver J, Kripke CM, Guare L, Sirugo G, Kember RL, Drivas TG, Dudek SM, Bradford Y, Lucas A, Judy R, Verma SS, Meagher E, Nathanson KL, Feldman M, Ritchie MD, Rader DJ, for The Penn Medicine BioBank: The Penn Medicine BioBank: Towards a Genomics-Enabled Learning Healthcare System to Accelerate Precision Medicine in a Diverse Population. J Pers Med 12(12): 1974, Nov 2022.

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Last updated: 07/02/2023
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