Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Mark Bi, Siming Zhao, Jonathan W. Said, Maria J. Merino, Adebowale J. Adeniran, Zuoquan Xie, Cayce B. Nawaf, Jaehyuk Choi, Arie S. Belldegrun, Allan J. Pantuck, Harriet M. Kluger, Kaya Bilgövar, Richard P. Lifton*, Brian Shuch

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10-4), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10-17); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence 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.

Original languageEnglish (US)
Pages (from-to)2170-2175
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number8
DOIs
StatePublished - Feb 23 2016

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Renal Cell Carcinoma
Neoplasms
Nucleotides
Loss of Heterozygosity
Mutation
BRCA1 Protein
Exome
Chromosomes, Human, Pair 9
Proteins
Neoplasm Genes
Phosphoric Monoester Hydrolases
Genes
Genome

ASJC Scopus subject areas

  • General

Cite this

Bi, Mark ; Zhao, Siming ; Said, Jonathan W. ; Merino, Maria J. ; Adeniran, Adebowale J. ; Xie, Zuoquan ; Nawaf, Cayce B. ; Choi, Jaehyuk ; Belldegrun, Arie S. ; Pantuck, Allan J. ; Kluger, Harriet M. ; Bilgövar, Kaya ; Lifton, Richard P. ; Shuch, Brian. / Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 8. pp. 2170-2175.
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title = "Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma",
abstract = "The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42{\%} of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10-4), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32{\%} of tumors (P = 5.47 × 10-17); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence 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.",
author = "Mark Bi and Siming Zhao and Said, {Jonathan W.} and Merino, {Maria J.} and Adeniran, {Adebowale J.} and Zuoquan Xie and Nawaf, {Cayce B.} and Jaehyuk Choi and Belldegrun, {Arie S.} and Pantuck, {Allan J.} and Kluger, {Harriet M.} and Kaya Bilg{\"o}var and Lifton, {Richard P.} and Brian Shuch",
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Bi, M, Zhao, S, Said, JW, Merino, MJ, Adeniran, AJ, Xie, Z, Nawaf, CB, Choi, J, Belldegrun, AS, Pantuck, AJ, Kluger, HM, Bilgövar, K, Lifton, RP & Shuch, B 2016, 'Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 8, pp. 2170-2175. https://doi.org/10.1073/pnas.1525735113

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. / Bi, Mark; Zhao, Siming; Said, Jonathan W.; Merino, Maria J.; Adeniran, Adebowale J.; Xie, Zuoquan; Nawaf, Cayce B.; Choi, Jaehyuk; Belldegrun, Arie S.; Pantuck, Allan J.; Kluger, Harriet M.; Bilgövar, Kaya; Lifton, Richard P.; Shuch, Brian.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 8, 23.02.2016, p. 2170-2175.

Research output: Contribution to journalArticle

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T1 - Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

AU - Bi, Mark

AU - Zhao, Siming

AU - Said, Jonathan W.

AU - Merino, Maria J.

AU - Adeniran, Adebowale J.

AU - Xie, Zuoquan

AU - Nawaf, Cayce B.

AU - Choi, Jaehyuk

AU - Belldegrun, Arie S.

AU - Pantuck, Allan J.

AU - Kluger, Harriet M.

AU - Bilgövar, Kaya

AU - Lifton, Richard P.

AU - Shuch, Brian

PY - 2016/2/23

Y1 - 2016/2/23

N2 - The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10-4), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10-17); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence 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.

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