Rigney Turnham

Interdisciplinary Training

Rigney Turnham

"Characterization of a chimeric transcript of PKA and DNAJB1 in FL-HCC"

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare cancer characterized by thick, fibrous
lamellae in the liver. A recent breakthrough in this untreatable cancer has come from whole-
genome sequencing of tumors from FL-HCC patients.  A 400kb deletion in chromosome 19
generates an in-frame fusion of heat shock protein 40 (DNAJB1) to most of a catalytic subunit of
protein kinase A (PKAC?). My working hypothesis is that fusion enzyme drives the progression
of FL-HCC.

I propose to address this new and important question in molecular cancer research by
combining the Scott lab’s interest in local PKA action with the clinical research expertise of Dr.
Yeung.  An attractive feature of this joint mentorship research project is the unique opportunity
to be trained by recognized experts in basic science and clinical medicine.

As a prelude to these studies I detected the expression of the slower migrating fusion protein
by immunoblot in lysates of resected FL-HCC tumors.  Preliminary immunofluoresce imaging
experiments infer that there may be enhanced membrane accumulation of PKA in tumor
sections.  Taken together these findings support an experimental plan of two specific aims that
1) compare the activity, binding properties and structure of the DNAJB1-PKAC? to wildtype PKA
and 2) measure PKA activity intrinsic to DNAJB1/HSP40 from FL-HCC patient samples and use
CRISPR technology to establish if an active DNAJB1-PKAC? fusion protein is a driver for FL-HCC
cancer progression. These studies should ascertain if DNAJB1-PKAC? confers oncogenic
properties on hepatocytes that result in FL-HCC.