Perelman School of Medicine at the University of Pennsylvania

Maxwell Lab

Projects

Project 1: Mechanisms of tumor formation in CHEK2 mutation carriers

Overview

Germline mutations in genes involved in DNA damage response, such as BRCA1 and BRCA2, are increasingly identified in patients with many different types of cancer including breast cancer. Full loss of BRCA1 or BRCA2 function results in deficiency in double strand break repair by homologous recombination (HR). HR deficient cells are unable to repair platinum-induced interstrand crosslinks and damage from poly-ADP-ribose polymerase (PARP) inhibitor stalled replication forks, leading to synthetic lethality. Therefore tumors associated with germline BRCA1/2 mutations have increased sensitivity to these agents.  CHEK2 is among the next most commonly mutated genes in breast cancer patients. Preclinical studies suggest CHEK2 deficient cells are also sensitive to PARP inhibitors due to their role in HR DNA repair, and clinical trials in patients with germline CHEK2 mutations are underway.

Methodology

In this project, we will utilize paired tumor-normal genomic profiling to study the relationship of DNA repair gene mutations to treatment response in breast cancer associated with germline CHEK2 mutations.

Collaborators

https://www.med.upenn.edu/apps/faculty/index.php/g275/p19464

https://www.med.upenn.edu/apps/faculty/index.php/g275/p9542

http://pathology.med.upenn.edu/department/people/945/anupma-nayak

http://pathology.med.upenn.edu/department/people/243/michael-d-feldman

 

Funding

https://www.cancer.gov/

https://www.bwfund.org/grant-programs/biomedical-sciences/career-awards-medical-scientists

 

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Project 2: Prostate Cancer Genetics

Overview

Recent studies have shown that 4-20% of prostate cancers are associated with germline mutations in DNA repair genes. Identification of these alterations may have clinical implications for personalized treatment of patients with prostate cancer. In addition, identification of an inherited mutation in a cancer affected patient can have far-reaching beneficial effects on reducing morbidity and mortality in his family members via implementation of cancer screening and prevention strategies. 

 

Currently, the majority of data on DNA repair gene mutational rates has been studied in metastatic prostate cancer patients.  As a result, the National Cancer Care Network supports germline genetic testing in metastatic prostate cancer patients with a family history suggestive of the associated syndrome, but there is currently no indication for testing in patients with localized prostate cancer.  Prior studies suggest a lower rate of DNA repair gene mutation positivity in localized prostate cancer patients, but few explore the differences in gene mutation rate for subsets of localized prostate cancer, for example by Gleason score.

 

Methodology

In this project we are utilizing paired tumor-normal genomic profiling to study the relationship of DNA repair gene mutations to Gleason score in localized prostate cancer patients in the Penn Medicine Biobank.  Additionally, we are determining the association of a number of candidate genes with prostate cancer risk.

Collaborators

Vivek K. Narayan, MD, MSCE

Lauren Ende Schwartz, MD

Daniel J. Lee, MD, MS

Penn Medicine BioBank

Funding

Penn Center for Precision Medicine

Basser Center for BRCA

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Project 3: Li-Fraumeni syndrome

Overview

Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caysed by inherited mutations in TP53.  Classic TP53 mutations confer an 80-90% lifetime risk of multiple types of cancer.  We and others have described a number of lower risk TP53 mutations, including an Ashkenazi Jewish predominant mutation, TP53 c.1000G>C;p.G334R.  Currently, surveillance for malignancy involves frequent laboratory and radiologic studies that are imperfect measures of disease onset; therefore, more specific, less invasive biomarker-driven screening methods are needed, particularly in patients with lower risk mutations. 

 

Methodology

In this multi-institutional study, we have an ongoing prospectively enrolling biobank of Li Fraumeni pediatric and adult patients.  We are collecting both tumor and normal tissues, and longitudinal plasma samples. 

Collaborators

Suzanne P. MacFarland, MD

Joshua Schiffman, MD

Brian Crompton, M.D.

Funding

ITMAT

 

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Project 4: Polygenic Risk Scores in Cancer

Overview

The prediction of patient outcomes in oncology relies on factors including pathological features, performance status, co-morbid conditions, and a variety of tumor molecular alterations.  Inherited genetic factors may also play a role in prediction of recurrence and overall survival in cancer patients.  Both rare and common genetic variation is associated with cancer risk and outcome; however, the contribution of individual common variants or single nucleotide polymorphisms (SNPs) is small. Weighted polygenic risk scores (PRS) combining multiple SNPs are associated with cancer risk in many cancers; however, it is unknown if PRS may be associated with outcomes in cancer.  However, to study this hypothesis, robust and high throughput methods of determining a patient’s course with regards to diagnosis, recurrence, and survival are needed.  This data is available from the Electronic Health Record (EHR) but requires the development of new computational tools to extract the data.

 

Methodology

In this project, we are developing a longitudinal patient profile for studying cancer risk, diagnosis, recurrence, and survival.   We will then determine if PRS are associated with DFS and OS in cancer patients within the Penn Medicine Biobank.

Collaborators

Danielle Mowery, PhD

Penn Medicine BioBank

Funding

Abramson Cancer Center Breakthrough Bike Challenge

 

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