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Sees patients age 4 to 65
Sees patients age 4 to 65
Recognized by America's Top Doctors 2015 – 2017
Recognized in Philadelphia magazine's annual Top Docs issues from 2018 - 2021
Perelman Center for Advanced Medicine
South Pavilion, 1st Floor
3400 Civic Center Boulevard
Philadelphia, PA 19104
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Hereditary Breast CancerThe 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 studies2) Characterization of moderate penetrance breast cancer susceptibility genes in large cohorts3) 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 scale5) Working with Dr. E. John Wherry’s group to elucidate immune function in healthy BRCA1/2 mutation carriersMelanomaOur 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 sequencing2) 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 groups4) 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 groupsTesticular Germ Cell TumorWe 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 evaluation2) HiChIP (chromosome conformation capture using few input cells) in fetal and adult germ cells to define target-enhancer connectome and identify causal variants for TGCT3) 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 TGCT5) Initiation and development of studies in non-whites with TGCT and women with ovarian germ tumors (also using social media)Neuroendocrine TumorsThe 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 disease2) Evaluation of whole genome sequencing of PCC/PGL patients with no identified inherited mutations3) 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
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): 119-124,2023.
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): 953-959,2022.
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): 2338-2350,2022.
Shah JB, Pueschl D, Wubbenhorst B, Fan M, Pluta J, D'Andrea K, Hubert AP, Shilan JS, Zhou W, Kraya AA, Llop Guevara A, Ruan C, Serra V, Balmaña J, Feldman M, Morin PJ, Nayak A, Maxwell KN, Domchek SM, Nathanson KL: Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers Nat Comm 13 (1): 6728,2022.
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 Online ahead of print : 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): 1974,2022.
Hakkaart C, Pearson JF, Marquart L, Dennis J, Wiggins GAR, Barnes DR, Robinson BA, Mace PD, Aittomäki K, Andrulis IL, Arun BK, Azzollini J, Balmaña J, Barkardottir RB, Belhadj S, Berger L, Blok MJ, Boonen SE, Borde J, Bradbury AR, Brunet J, Buys SS, Caligo MA, Campbell I, Chung WK, Claes KBM; GEMO Study Collaborators; EMBRACE Collaborators, Collonge-Rame MA, Cook J, Cosgrove C, Couch FJ, Daly MB, Dandiker S, Davidson R, de la Hoya M, de Putter R, Delnatte C, Dhawan M, Diez O, Ding YC, Domchek SM, Donaldson A, Eason J, Easton DF, Ehrencrona H, Engel C, Evans DG, Faust U, Feliubadaló L, Fostira F, Friedman E, Frone M, Frost D, Garber J, Gayther SA, Gehrig A, Gesta P, Godwin AK, Goldgar DE, Greene MH, Hahnen E, Hake CR, Hamann U, Hansen TVO, Hauke J, Hentschel J, Herold N, Honisch E, Hulick PJ, Imyanitov EN; SWE-BRCA Investigators; kConFab Investigators; HEBON Investigators, Isaacs C, Izatt L, Izquierdo A, Jakubowska A, James PA, Janavicius R, John EM, Joseph V, Karlan BY, Kemp Z, Kirk J, Konstantopoulou I, Koudijs M, Kwong A, Laitman Y, Lalloo F, Lasset C, Lautrup C, Lazaro C, Legrand C, Leslie G, Lesueur F, Mai PL, Manoukian S, Mari V, Martens JWM, McGuffog L, Mebirouk N, Meindl A, Miller A, Montagna M, Moserle L, Mouret-Fourme E, Musgrave H, Nambot S, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nguyen-Dumont T, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Osorio A, Ott CE, Park SK, Parsons MT, Pedersen IS, Peixoto A, Perez-Segura P, Peterlongo P, Pocza T, Radice P, Ramser J, Rantala J, Rodriguez GC, Rønlund K, Rosenberg EH, Rossing M, Schmutzler RK, Shah PD, Sharif S, Sharma P, Side LE, Simard J, Singer CF, Snape K, Steinemann D, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teo SH, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Trainer AH, Tripathi V, Tung N, van Engelen K, van Rensburg EJ, Vega A, Viel A, Walker L, Weitzel JN, Wevers MR, Chenevix-Trench G, Spurdle AB, Antoniou AC, Walker LC: Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers Commun Biol 5 (1): 1061,2022.
Stejerean-Todoran I, Gimotty PA, Watters A, Brafford P, Krepler C, Godok T, Li H, Bonilla Del Rio Z, Zieseniss A, Katschinski DM, Sertel SM, Rizzoli SO, Garman B, Nathanson KL, Xu X, Chen Q, Oswald JH, Lotem M, Mills GB, Davies MA, Schön MP, Bogeski I, Herlyn M, Vultur A: A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells Neuro Oncol Online ahead of print : 2022.
Grasso C, Popovic M, Isaevska E, Lazzarato F, Fiano V, Zugna D, Pluta J, Weathers B, D'Andrea K, Almstrup K, Anson-Cartwright L, Bishop DT, Chanock SJ, Chen C, Cortessis VK, Dalgaard MD, Daneshmand S, Ferlin A, Foresta C, Frone MN, Gamulin M, Gietema JA, Greene MH, Grotmol T, Hamilton RJ, Haugen TB, Hauser R, Karlsson R, Kiemeney LA, Lessel D, Lista P, Lothe RA, Loveday C, Meijer C, Nead KT, Nsengimana J, Skotheim RI, Turnbull C, Vaughn DJ, Wiklund F, Zheng T, Zitella A, Schwartz SM, McGlynn KA, Kanetsky PA, Nathanson KL, Richiardi L: Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk Cancer Epidemiol Biomarkers Prev 31 (9): 1769-1779,2022.
Gray GK, Li CM, Rosenbluth JM, Selfors LM, Girnius N, Lin JR, Schackmann RCJ, Goh WL, Moore K, Shapiro HK, Mei S, D'Andrea K, Nathanson KL, Sorger PK, Santagata S, Regev A, Garber JE, Dillon DA, Brugge JS: A human breast atlas integrating single-cell proteomics and transcriptomics Dev Cell 57 (11): 1400-1420,2022.
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