Date of Award
Open Access Thesis
Medical Doctor (MD)
Richard P. Lifton
The presence of sarcomatoid features in renal cell carcinoma (ccRCC) confers a poor prognosis. The mechanisms that account for these sarcomatoid features are unknown. We performed whole exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining 19 tumors, sarcomatoid and carcinomatous elements shared a mean of 45/108 (41.7%) somatic single nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs 63 SSNVs, p=4.0x10-4), increased frequency of non-synonymous SSNVs in Pan-Cancer genes (mean 1.4 vs 0.26, p=0.002), and increased frequency of loss of heterozygosity across the genome (median 913 vs 460 Mb in LOH, p < 0.05), with significant recurrent segments of LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent somatic mutations shared by carcinomatous and sarcomatoid elements were in known ccRCC genes (VHL, PBRM1, SETD2, PTEN). Most interestingly, sarcomatoid elements acquired new bi-allelic TP53 mutations in 32% of tumors (p=5.47x10-17); TP53 mutations were absent in carcinomatous elements in non-hypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ARID1A and BAP1 were significantly mutated in sarcomatoid elements, and were mutually exclusive with TP53 and each other. Additionally, LOH on chromosome 9 was found in all TP53-mutant tumors. These findings demonstrate that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.
Bi, Xiao, "Genomic Characterization Of Sarcomatoid Transformation In Clear Cell Renal Cell Carcinoma" (2016). Yale Medicine Thesis Digital Library. 2039.