David Starks

Symptoms and health related quality of life in patients receiving matched therapy.

e21648Background: Genomic sequencing is increasingly being used to select targeted agents that are matched to molecular alterations. Potential differences in symptom occurrence and severity as well...

Comprehensive molecular profiling of advanced gynecologic malignancies.

e17082Background: Precision medicine has been studied in patients with advanced, heavily-treated cancers by administering molecularly targeted monotherapies. Rational combination approaches that ar...

Abstract 2463: Tumor profiling of separated carcinomatous and sarcomatous components from uterine carcinosarcoma biopsies provides insights into their development

Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinomatous) and mesenchymal (sarcomatous) elements. Studies have indicated that UCS arises from sarcomatous differentiation of high-grade carcinoma while others have suggested a bi-clonal nature. Given these differences, we sought to separate the carcinoma and sarcoma elements of UCS to try to understand their molecular differences and gain further insights into how these tumors develop. We macrodissected carcinomatous, sarcomatous, and normal cells from formalin fixed paraffin embedded (FFPE) uterine samples of 10 UCS patients. DNA and RNA were isolated and extracted using the Qiagen AllPrep DNA/RNA FFPE kit. Whole-genome SNP microarrays and deep sequencing of 26 cancer genes was performed, using the Illumina Infinium OmniExpressExome array and the TruSight Tumor panel respectively. Illumina HiSeq mRNA sequencing was also performed to quantify gene expression. The genomic allelic imbalance (AI) profiling, called from the SNP data by hapLOH, showed that sarcoma samples were more aberrant than their carcinoma counterparts (abstract 131, AACR 2016). From the targeted sequencing, the Illumina Amplicon-DS Somatic Variant Caller was employed to call somatic mutations. Mutations were identified in TP53 in both the sarcoma and carcinoma samples of all 10 patients. Frequently mutated genes included APC, EGFR, MET and MSH6 which were found in 60-80% of the patients. Genes mutated in less than 50% of the patients included PTEN, KRAS, KIT, FBXW7, PIK3CA, FGFR2, and CTNNB1. Current results showed no association of a mutated gene to either the sarcoma or carcinoma component of UCS. RSEM, STAR and EBSeq were applied to the RNA-seq data for gene expression quantification. Approximately 2500 genes were identified as being differentially expressed (DE) between normal and carcinoma samples. Just over 4000 genes were identified as being DE between normal and sarcoma samples. 75% of the DE genes in the carcinoma were also identified in the sarcoma. Using DAVID functional annotation tool, we characterized these gene sets with KEGG pathways. Deregulated pathways identified in both carcinoma and sarcoma include: cell cycle, transcriptional regulation, Ras and p53 signaling. Some additional pathways are putatively associated with sarcoma only, including MAPK and PI3K-Akt signaling. We report here the differences between sarcoma and carcinoma components of UCS from multiple molecular perspectives. From the genomic AI and DE analysis, the carcinoma aberrations appear to be mostly a subset of the sarcoma tumor profiles, where sarcoma samples appear to be more highly aberrant compared to the carcinoma samples. One possible inference from this is that the sarcoma originated and evolved from the carcinoma cells. Citation Format: Yihua Liu, Zachary Weber, F. Anthony San Lucas, Aditya Deshpande, Raed Sulaiman, Mary Fagerness, Natasha Flier, Joseph Sulaiman, Christel M. Davis, Jerry Fowler, Gareth E. Davies, David Starks, Luis Rojas-Espaillat, Paul Scheet, Erik A. Ehli. Tumor profiling of separated carcinomatous and sarcomatous components from uterine carcinosarcoma biopsies provides insights into their development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2463. doi:10.1158/1538-7445.AM2017-2463

Oncologic outcomes of advanced gynecologic malignancies managed with the aid of comprehensive genomic profiling (CGP) in a rural community setting.

e17077Background: Managing advanced gynecologic malignancies represents a challenge. Chemotherapies for recurrent disease have limited efficacy, as they are selectied ignoring the role that tumor h...

Abstract 131: Allelic imbalance analysis of uterine carcinosarcoma: An inquiry into the dual nature of the neoplasm

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Uterine carcinosarcoma (UCS), also known as Malignant Mixed Mullerian Tumor, is a neoplasm of the female genital tract that shows histological features of both carcinoma and sarcoma. Some studies have indicated that UCS arises from sarcomatous differentiation of high-grade carcinoma while others have confirmed a bi-clonal nature of the tumor. Given these differences, further investigation in the origin of this tumor with newer approaches and technologies is warranted. In this study we determined the allelic imbalance (AI) profiles of the two components of UCS and compared the AI events that were shared by, or differed between, them. Samples were obtained from 10 patients diagnosed with UCS and were preserved in formalin fixed paraffin embedded (FFPE) blocks. The two components (carcinoma & sarcoma) were identified and micro-dissected, and whole-genome DNA micro-arrays were applied to the isolated DNA. We then applied a sensitive computational method that combines haplotype information with SNP array data to identify somatic segmental copy number variations and copy-neutral loss of heterozygosity (cnLOH). After we obtained the AI events we filtered small events (<2 MB) to rule out germline duplications. We then obtained events that are common to both components by using a criterion of 80% reciprocal overlap. All such events were classified as a gain, loss or cnLOH. We found that, on an average, 80% of the events found in the carcinoma component are common with the sarcoma component. Conversely, only 64% of events seen in the sarcoma component are found in the carcinoma. This may be in part due to the fact that the sarcoma component usually showed greater number of events and most of these events were larger than the corresponding carcinoma component. Also the sarcoma component showed an increased degree of allelic imbalance than the counterpart. We then looked into particular regions of known tumor suppressor and oncogenes and identified loss in the TP53 gene region (60% of tumors), gains in PIK3CA and PTEN gene regions (40% of tumors), among other events. Our analysis showed that the sarcomatous component shared major portions of the AI profile with the carcinomatous component, but also showed additional events and a greater degree of AI. One explanation for this observation can be that the sarcomatous component retains the AI profile of the carcinomatous component and also gathers additional imbalance. This suggests directionality to the development of UCS: that it arises by sarcomatous differentiation of already existing carcinoma of the uterus. We are pursuing additional assessments of point mutations and expression profiles to complement our existing analyses. Citation Format: Aditya S. Deshpande, Zachary Weber, Raed Sulaiman, Natasha Flier, Cheryl Ageton, Mary Fagerness, Joseph Sulaiman, Gareth E. Davies, David Starks, Luis Rojas-Espaillat, Paul A. Scheet, Erik Ehli. Allelic imbalance analysis of uterine carcinosarcoma: An inquiry into the dual nature of the neoplasm. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 131.