Molecular Oncology and Biomarkers


HawthornLesleyann Hawthorn, PhD

Professor of Pathology

Director Cancer Center Shared Resources

Molecular Oncology and Biomarkers Program

 

Georgia Cancer Center
1410 Laney Walker Blvd., CN-2135
Phone:
706-721-4384 office 706-721-5471 laboratory
Email: lhawthorn@augusta.edu

Research Summary

The primary focus of Dr. Hawthorn’s research is global genetic profiling of cancers and cancer patients. Her group uses a variety of genomics technologies to examine the genetic alterations which drive cancer initiation and progression. These include next generation sequencing to examine chromosomal copy number alterations, mutation analysis, transcript expression analysis and genome-wide association studies.

Research Interests

Mutational Analysis of Triple Negative Breast Cancer in African American Patients.Women of African descent (AA) have a generally lower rate of breast cancer incidence than women of European descent (CA) but a paradoxically higher rate of mortality . Epidemiological studies have reported that the mortality rate of breast cancer patients is approximately 30-40% higher in AA patients. It has been hypothesized that the poorer outcomes of AA patients were related to differences in socio-economic factors however, recent findings suggest that these differences in clinical outcomes conceivably arise from an interaction of environmental and genetic factors.

Triple negative breast cancer (TNBC) is molecularly defined by the absence of detectable estrogen and progesterone receptor expression levels and by the lack of the epidermal growth factor receptor 2 (HER2/ERBB2) gene amplification. The TNBC phenotype accounts for 15% of CA breast cancer patients and approximately 30% of tumors in AA patients. TNBC in AA patients has a more aggressive clinical course including a higher mortality rate and an increased occurrence of metastases. This study was designed to determine if racial differences at the molecular level might explain the more aggressive phenotype in AAs. Mutation profiling, was performed on tumors from both racial groups using whole exome sequencing. Transcript expression analysis was  also performed on tumors from both racial groups.  African Americans had a more variable mutation profile with a larger number of genetic variants per patient and a larger number of different variant-containing genes, while CA samples had a fewer number of variant-containing genes and lower numbers of deleterious variants per patient. We also found that genes with high frequency mutation rates such as MUC4 and TP53 were common to both racial populations, however genes that were less frequently mutated differed between the races suggesting that those cause the more aggressive nature of TNBC in AA women. JAK-Stat and HER2 signaling were unique to the AA and PTEN and mTOR were unique to the CA profiles. Many pathways identified by the mutational profiles were predicted to be down-regulated by the transcript expression profiles.

 Our study is now examining if the mutations discovered are also detectable in circulating tumor DNA.

 Wilms Tumor and Mutations in Cilia-related genes

Wilms tumor is the most common pediatric renal tumor and the fourth most common malignancy in children. Chromosome 16q deletion(del) or loss of heterozygosity (LOH) has been correlated with recurrence and overall poor prognosis, such that patients with 16qdel/LOH are treated with more aggressive chemotherapeutic regimens.  In the present study, we have compared the mutational profiles of Wilms tumors with and without 16q del/LOH using both data available from the TARGET database and tumors procured from our legacy collection. Exome-Seq data was analyzed for tumor specific-mutations and a large number of cilia-related genes mapping to 16q were found to carry mutations specific to those  tumors with 16qdel/LOH. 

Whole exome analyses further revealed a large number of cilia-related genes across the genome were mutated in tumors both with and without 16qdel/LOH. Additional pathway analyses revealed that many cilia-related pathway members were also mutated in these tumors including Sonic Hedgehog (SHh), Wnt, and Notch signaling pathways. The data suggest that cilia-related genes and pathways are compromised in Wilms tumors. The mutated cilia-related genes on chromosome 16q may account for the more aggressive nature of tumors with 16q del/LOH.

Colorectal cancer
Colorectal cancer (CRC) is the result of a multi-step progression and accumulation of genetic alterations. The term "field cancerization" has been used to describe pre-malignant tissue in which new cancers are more likely to arise, and the concept of field cancerization in clinical oncology has received increasing attention. This interest is further motivated by the exceedingly high incidence of second primary colorectal cancers occurring in approximately 300 to 400/100,000 patients. In the colon, this field of cancerization hypothesis is the rationale for colonoscopic post-polypectomy surveillance. Aside from the adenomatous polyp, there have been a number of putative biomarkers that occur earlier in the pre-dysplastic mucosa. These include gains, amplifications, losses, deletions and translocations which are the hallmarks of chromosomal instability observed in most tumor types. Copy number alterations (CNAs) typically seen in colorectal tumors may occur in low-grade dysplastic adenomas are therefore proposed as major factors in tumorigenesis.

One such study from the Hawthorn lab compared transcript expression, and chromosomal changes on a series of tumors and surrounding tissues to determine if there is evidence of field cancerization in colorectal cancer. Epithelial cells were isolated from tumors and areas adjacent to the tumors ranging from 1-10 cm. Tumor abnormalities mirrored those previously reported for colon cancer and while the number and size of the chromosomal abnormalities were greatly reduced in cells from surrounding regions, many copy number and LOH events were discernable. Interestingly, these abnormalities were not consistent across the field in the same patient samples suggesting a field of chromosomal instability surrounding the tumor. A mutator phenotype has been proposed to account for this instability which states that the genotypes of most cells within a tumor would not be identical, but would share at least a single mutation in any number of genes, or a selection of genes affecting a specific pathway which provide a proliferative advantage.

Selected Publications

Chang, C.S., Kitamura, E., Johnson, J., Bollag, R. and Hawthorn, L.  (2018). Genomic analysis of racial differences in triple negative breast cancer. Genomics.PMID:30366040

Kitamura K,  Cowell JK, Chang C, Hawthorn L.  (2019). Mutational Analysis of Chromosome 16q Loss in Wilms Tumors Reveals Link to Cilia- Related Genes and Pathways. Genes Chrom Cancer, (in press)

Hawthorn Land Cowell J. (2011). Analysis of Wilm’s Tumors using SNP mapping array-based Comparative Genomic Hybridization. PLOS One 6:4-14, .

Hawthorn L, Lan L, Mojica W. (2014) Evidence for Field Effect Cancerization in Colorectal Cancer. Genomics.103: 211-21.

Mojica W, Hawthorn L. (2010) Normal colon epithelium: a dataset for the analysis of gene expression and alternative splicing events in colon disease. BMC Genomics. 11:5-19.

Hu, T., Chong, Y., Lu, S., Wang, R., Qin, H., Silva, J., Kitamura, E., Chang, C.S., Hawthorn, L. and Cowell, J.K. (2018) miR-339 Promotes Development of Stem Cell Leukemia/Lymphoma Syndrome via Downregulation of the BCL2L11 and BAX Proapoptotic Genes. Cancer Res, 78, 3522-3531.

 Silva, J., Chang, C.S., Hu, T., Qin, H., Kitamura, E., Hawthorn, L., Ren, M. and Cowell, J.K. (2018) Distinct signaling programs associated with progression of FGFR1 driven leukemia in a mouse model of stem cell leukemia lymphoma syndrome. Genomics.

 Duff, M.C., Kuhne, W.W., Halverson, N.V., Chang, C.S., Kitamura, E., Hawthorn, L., Martinez, N.E., Stafford, C., Milliken, C.E., Caldwell, E.F. et al. (2014) mRNA Transcript abundance during plant growth and the influence of Li(+) exposure. Plant Sci, 229, 262-279.