Biomedical Graduate Studies

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

Melanoma
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