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Recognized by America's Top Doctors 2015 – 2017
Recognized in Philadelphia magazine's annual Top Docs issues from 2018 - 2020
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
Alzofon N, Koc K, Panwell K, Pozdeyev N, Marshall CB, Albuja-Cruz M, Raeburn CD, Nathanson KL, Cohen DL, Wierman ME, Kiseljak-Vassiliades K, Fishbein L: Mastermind Like Transcriptional Coactivator 3 (MAML3) Drives Neuroendocrine Tumor Progression Mol Cancer Res
Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL; GEMO Study Collaborators; EMBRACE Collaborators, Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, Hunter DJ, Imyanitov EN; KConFab Investigators; HEBON Investigators; ABCTB Investigators, Jager A, Jakubowska A, James PA, Jensen UB, John EM, Jones ME, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khusnutdinova E, Kiiski JI, Ko YD, Kosma VM, Kraft P, Kurian AW, Laitman Y, Lambrechts D, Le Marchand L, Lester J, Lesueur F, Lindstrom T, Lopez-Fernández A, Loud JT, Luccarini C, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Mebirouk N, Meindl A, Miller A, Milne RL, Montagna M, Nathanson KL, Neuhausen SL, Nevanlinna H, Nielsen FC, O'Brien KM, Olopade OI, Olson JE, Olsson H, Osorio A, Ottini L, Park-Simon TW, Parsons MT, Pedersen IS, Peshkin B, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Polley EC, Poppe B, Presneau N, Pujana MA, Punie K, Radice P, Rantala J, Rashid MU, Rennert G, Rennert HS, Robson M, Romero A, Rossing M, Saloustros E, Sandler DP, Santella R, Scheuner MT, Schmidt MK, Schmidt G, Scott C, Sharma P, Soucy P, Southey MC, Spinelli JJ, Steinsnyder Z, Stone J, Stoppa-Lyonnet D, Swerdlow A, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Teulé A, Thull DL, Tischkowitz M, Toland AE, Torres D, Trainer AH, Truong T, Tung N, Vachon CM, Vega A, Vijai J, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wolk A, Yadav S, Yang XR, Yannoukakos D, Zheng W, Ziogas A, Zorn KK, Park SK, Thomassen M, Offit K, Schmutzler RK, Couch FJ, Simard J, Chenevix-Trench G, Easton DF, Andrieu N, Antoniou A: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers Nat Commun 12 (1): 1078,2021.
Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J, Gao C, Lilyquist J, Yadav S, Boddicker NJ, Samara R, Klebba J, Ambrosone CB, Anton-Culver H, Auer P, Bandera EV, Bernstein L, Bertrand KA, Burnside ES, Carter BD, Eliassen H, Gapstur SM, Gaudet M, Haiman C, Hodge JM, Hunter DJ, Jacobs EJ, John EM, Kooperberg C, Kurian AW, Le Marchand L, Lindstroem S, Lindstrom T, Ma H, Neuhausen S, Newcomb PA, O'Brien KM, Olson JE, Ong IM, Pal T, Palmer JR, Patel AV, Reid S, Rosenberg L, Sandler DP, Scott C, Tamimi R, Taylor JA, Trentham-Dietz A, Vachon CM, Weinberg C, Yao S, Ziogas A, Weitzel JN, Goldgar DE, Domchek SM, Nathanson KL, Kraft P, Polley EC, Couch FJ: A Population-Based Study of Genes Previously Implicated in Breast Cancer N Engl J Med 384 (5): 440-451,2021.
Greenberg SE, Jacobs MF, Wachtel H, Anson A, Buchmann L, Cohen DL, Bonanni M, Bennett B, Naumer A, Schaefer AM, Kohlmann W, Nathanson KL, Else T, Fishbein L: Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome Genet Med 22 (12): 2101-07,2020.
Wachtel H, Hutchens T, Baraban E, Schwartz LE, Montone K, Baloch Z, LiVolsi V, Krumeich L, Fraker DL, Nathanson KL, Cohen DL, Fishbein L: Predicting Metastatic Potential in Pheochromocytoma and Paraganglioma: A Comparison of PASS and GAPP Scoring Systems J Clin Endocrinol Metab
105 (12): 2020.
Katona BW, Powers J, McKenna DB, Long JM, Le AN, Hausler R, Zelley K, Jennings S, Domchek SM, Nathanson KL, MacFarland SP, Maxwell KN: Upper Gastrointestinal Cancer Risk and Surveillance Outcomes in Li-Fraumeni Syndrome Am J Gastroenterol
115 (12): 2095-2097,2020.
Palmer JR, Polley EC, Hu C, John EM, Haiman C, Hart SN, Gaudet M, Pal T, Anton-Culver H, Trentham-Dietz A, Bernstein L, Ambrosone CB, Bandera EV, Bertrand KA, Bethea TN, Gao C, Gnanaolivu RD, Huang H, Lee KY, LeMarchand L, Na J, Sandler DP, Shah PD, Yadav S, Yang W, Weitzel JN, Domchek SM, Goldgar DE, Nathanson KL, Kraft P, Couch FJ: Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women J Natl Cancer Inst 112 (12): 1213-1221,2020.
Nead KT, Mitra N, Weathers B, Pyle L, Emechebe N, Pucci DA, Jacobs LA, Vaughn DJ, Nathanson KL, Kanetsky PA: Lower abdominal and pelvic radiation and testicular germ cell tumor risk PLoS One 15 (11): 2020.
Nguyen MQ, Teh JLF, Purwin TJ, Chervoneva I, Davies MA, Nathanson KL, Cheng PF, Levesque MP, Dummer R, Aplin AE: Targeting PHGDH upregulation reduces glutathione levels and re-sensitizes resistant NRAS mutant melanoma to MEK inhibition J Invest Dermatol 140 (11): 2242-2252,2020.
Vasta LM, McMaster ML, Harney LA, Ling A, Kim J, Harris AK, Carr AG, Damrauer SM, Rader DJ, Kember RL, Kanetsky PA, Nathanson KL, Pyle LC, Greene MH, Schultz KA, Stewart DR; Regeneron Genetics Center (RGC) Research Team: Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors Cancer Genet 248–249 : 49-56,2020.
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