TY - JOUR
T1 - Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma
AU - Casuscelli, Jozefina
AU - Weinhold, Nils
AU - Gundem, Gunes
AU - Wang, Lu
AU - Zabor, Emily C.
AU - Drill, Esther
AU - Wang, Patricia I.
AU - Nanjangud, Gouri J.
AU - Redzematovic, Almedina
AU - Nargund, Amrita M.
AU - Manley, Brandon J.
AU - Arcila, Maria E.
AU - Donin, Nicholas M.
AU - Cheville, John C.
AU - Thompson, R. Houston
AU - Pantuck, Allan J.
AU - Russo, Paul
AU - Cheng, Emily H.
AU - Lee, William
AU - Tickoo, Satish K.
AU - Ostrovnaya, Irina
AU - Creighton, Chad J.
AU - Papaemmanuil, Elli
AU - Seshan, Venkatraman E.
AU - Hakimi, A. Ari
AU - Hsieh, James J.
N1 - Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
AB - Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
UR - http://www.scopus.com/inward/record.url?scp=85032164632&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.92688
DO - 10.1172/jci.insight.92688
M3 - Article
C2 - 28614790
AN - SCOPUS:85032164632
SN - 2379-3708
VL - 2
JO - JCI Insight
JF - JCI Insight
IS - 12
M1 - e92688
ER -