The ASC Foundation funds projects relevant to clinical cytopathology practice, translational research for new technologies in cytopathology and best practices in cytopathology.
The ASC Foundation Young Investigator Grant consists of a $50,000 Research Grant awarded to the successful applicant. The Grant is designed to fund young investigators in the discovery of new knowledge related to the advancement of cytopathology. The top three proposals presented their research projects to a panel of judges during the 2017 ASC Annual Scientific Meeting in Phoenix, Arizona at the Cytology Shark Tank. Dr. Vivian Weiss of Vanderbilt University was selected the winner. Below is an update on Dr. Weiss’ project.
The Use of Next Generation Sequencing to Identify the Molecular and Immunologic Mechanisms of Thyroid Cancer Invasion to Develop Improved FNA-based Testing
Vivian Weiss, MD, PhD
Vanderbilt University Medical Center
Being awarded the 2017 ASC Foundation Young Investigator Grant at the Cytology Shark Tank Competition has enabled my laboratory to begin identifying new molecular and immunology markers of thyroid cancer. Our goal is to use next generation sequencing (NGS) and innovative computational techniques to identify immune cell subtypes and novel mutations that are markers of thyroid malignancy. Our first step was to determine if a publically available database, such as The Cancer Genome Atlas (TCGA) could provide clues to the immunologic markers in thyroid cancer. We evaluated ~500 papillary thyroid carcinomas (PTCs) that have undergone RNA sequencing and whole exome sequencing using computational immunogenomics. This analysis revealed activated dendritic cells in the tumor microenvironment correlate significantly with increased pathologic tumor stage and the lymph node metastases. Additionally, we found that follicular helper T cells in the tumor microenvironment correlated with lower pathologic stage and follicular histology. We are excited to report that this work has been submitted for publication.
However, analysis of the TCGA alone provides insufficient information to make further advances in diagnosing indeterminate thyroid nodules. There is limited clinical information maintained in the TCGA database and it does not contain a wide variety of thyroid lesions. Can noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) be distinguished from invasive follicular variant of papillary thyroid carcinoma? Can follicular adenoma be distinguished from minimally invasive follicular carcinoma? Can an aggressive papillary thyroid carcinomas be distinguished from those with more indolent behavior? None of these questions could be thoroughly investigated using only the TCGA. Therefore, we determined the need to sequence our own expanded cohort.
The generous funding provided by the ASC Foundation has allowed my laboratory to compile and sequence a larger, more comprehensive cohort to help answer these questions. We collected a cohort of 200 thyroids resected at Vanderbilt University Medical Center. These resection specimens include non-neoplastic thyroids (including those with Hashimoto’s thyroiditis), classical PTCs (including those with Hashimoto’s thyroiditis), follicular variant PTCs, NIFTP, follicular adenomas (including oncocytic type), follicular carcinomas (including oncocytic type), poorly differentiated thyroid carcinomas, and anaplastic thyroid carcinomas. Some patients within this cohort have multiple specimens collected at various timepoints, including distant metastasis, recurrence, and de-differentiation. Sequencing these specimens will provide an assessment of disease evolution and progression overtime.
How will this cohort add to the literature and advance thyroid cancer diagnosis and treatment? First, the cohort contains an array of different thyroid lesions, not just PTC. Second, we are performing 200x whole exome sequencing, which will provide more sequencing depth than TCGA. This increased depth allows for detection of small tumor clones that may be responsible for invasion, metastasis, or recurrence. We have paired normal tissue for each of these specimens so that we can control for germline mutations. Finally, the RNA sequencing allows us to evaluate gene expression changes, fusions, and tumor immune infiltration. Through the evaluation of the molecular and immunologic alterations across a variety of benign and malignant thyroid lesions, we will identify key markers of invasion, metastasis, and tumor aggression. This knowledge can them be used to improve both thyroid cancer diagnosis and treatment.
It has been nine months since I received ASC Foundation funding. The entire cohort has been sequenced, and we are now performing the bioinformatics pipeline necessary to analyze all of that data. This involves aligning all of the small fragments of sequenced genetic material to a reference genome. All alignments must then be checked for quality. Finally, the mutations or transcript counts must be carefully analyzed. We hope to have all of this data analyzed by 2019 and will be excited to share all that the Weiss laboratory has discovered!
It has been invaluable to have the support of the ASC leadership, its members, and the ASC Foundation. The ASC Foundation Young Investigator Grant has made it possible for me to develop this exciting research program and launch my career as an independent physician-scientist. I am very grateful. Good luck to the next ASC Shark Tank grant recipient! I know you will find the ASC Foundation funding instrumental as you grow your research program and your career.
The ASC Foundation Investigator Grant – Cytology Shark Tank is back for 2018! The event will take place on Monday, November 12 at 4:30 pm in the Regency Ballroom of the Omni Shoreham Hotel in Washington, DC. Again this year, Dr. Liron Pantanowitz returns as the moderator. The Sharks this year are William C. Faquin, MD, PhD, Dina R. Mody, MD, Vivian L. Weiss, MD, PhD, and David C. Wilbur, MD
Watch as three worthy finalists give a three-minute pitch to the pesky panel of tough sharks. Who will the “Sharks” deem worthy of a $50,000 research grant?
This year’s contestants are:
Alarice Lowe, MD
Brigham and Women’s Hospital
Proposal: Advancing Cytology through the Integration of Rare Cell Technology
Dianna Ng, MD
University of California, San Francisco
San Francisco, California
Proposal: Fine Needle Aspiration Biopsy for Cell Surface Proteomics: Towards a Personalized Cancer “Surfaceome”
Kaitlin Sundling, MD, PhD
University of Wisconsin Hospital & Clinics
Proposal: Development of a Deep Learning Image Analysis System for Improved Cytology Screening
Be there to support and encourage our three finalists as they dive into the ASC Cytology Shark Tank!