ER+ luminal tumors are the most frequent subtype of breast cancer. Stat1−/− mice develop mammary tumors that closely resemble this cancer subtype. To identify transforming events that contribute to tumorigenesis, we performed whole genome sequencing of Stat1−/− primary mammary tumors and matched normal tissues. This investigation identified somatic truncating mutations affecting the prolactin receptor (Prlr) in all tumor samples. Targeted sequencing confirmed the presence of these mutations in precancerous lesions, indicating this is an early event in tumorigenesis. Functional evaluation showed that co-expression of truncated and wild type Prlr led to aberrant Stat3 and Stat5 activation downstream of the receptor, cellular transformation in vitro and tumor formation in vivo.
Obi Griffith, Malachi Griffith, Kilannin Krysiak, Zachary Skidmore, Jasreet Hundal, Lee Trani
We report the first comprehensive genomic analysis of a case of Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC). No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples. These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.
Obi Griffith, Malachi Griffith, Kilannin Krysiak, Avinash Ramu, Zachary Skidmore, Jason Kunisaki
Comprehensive genomic analysis was performed on patient derived xenografts for oral squamous cell carcinomas (OSCC). We found PDX samples were largely correlative with the primary tumors from which they were derived. PDX models were able to retain the heterozygous mutational landscape and clonal architecture of tumors. Somatic differences between the PDX and corresponding OSCC primary samples consited primarily of low-frequency mutations making these xenografts ideal models for exploring OSCC tumor biology.
Katie Campbell, Zachary Skidmore, Erica Barnell, Malachi Griffith, Obi Griffith
In support of several clinical trials we are creating and applying new immunogenomics tools to help predict response to checkpoint blockade inhibition therapies and design personalized cancer vaccines.
Jasreet Hundal, Katie Campbell, Yang-Yang Feng, Connor Liu, Joshua McMichael, Susanna Kiwala, Obi Griffith, Malachi Griffith
Extensive genomic analyses were performed in an adult with post-allo relapsed B-ALL. Mutations were found in EP300, NF1, IKZF1, SETD2, RB1, PAX5, NF1, ETV6, and ZNF384. Transcriptome analysis identified aberrant overexpression of the FLT3 gene. Treatment with the FLT3 inhibitor sunitinib induced a rapid clinical and molecular response. This study demonstrates a powerful proof-of-principle that comprehensive genomic studies can sometimes reveal unexpected clinically actionable therapeutic targets.
Griffith et al. 2016. Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia. Experimental Hematology. 44(7):603-13.
Malachi Griffith, Obi Griffith, Kilannin Krysiak, Zachary Skidmore, Avinash Ramu, Alex Wagner, Katie Campbell, Robert Lesurf, Jasreet Hundal, Nicholas Spies, Benjamin Ainscough, Jason Walker