Kenneth Matreyek

Interdisciplinary Training

Kenneth Matreyek

"Comprehensive Interpretation of Tumor Suppressor Variation in Cancer"

Cancer patients can now get their tumors sequenced, but the multitudes of genetic variations
in tumors makes it difficult to identify the cancer-promoting “driver” mutations from the
relatively innocuous “passenger” mutations. These variations are too numerous and resource-
intensive to study individually, and computational algorithms remain unacceptably inaccurate
for routine use in the clinic. Many cancer patients and carriers of variations in cancer-related
genes are left wondering how their variants will affect their health. Thus, there is a critical need
for connecting sequence information with clinical outcome, since it will allow us to take actions
to help these individuals.

I will fill this need by simultaneously measuring the consequences of every possible missense
variant of a cancer protein. I will focus on the tumor suppressor PTEN, mutated in diverse
cancers including prostate cancer, glioblastoma, and endometrial cancer. Working with my
mentor, Dr. Douglas Fowler, I will create comprehensive datasets describing how each PTEN
variant influences various oncogenic processes, such as uncontrolled cell proliferation and
survival. Subsequently, working with my co-mentor Dr. Brian Shirts, I will develop an algorithm
that accurately predicts the pathogenic consequences of variations observed in the clinic.

The information I collect on PTEN will allow clinicians to distinguish cancer “driver” from
“passenger” mutations, which help them to accurately assess patient disease risk and tailor
patient-specific treatment regiments. The tools and strategies I develop will be applicable to
other tumor suppressor proteins, and will create a framework for fully harnessing the power of
cancer genomics to attack cancer.