Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma.
Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.
Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Siming
S
Zhao
Murim
M
Choi
John D
JD
Overton
Stefania
S
Bellone
Dana M
DM
Roque
Emiliano
E
Cocco
Federica
F
Guzzo
Diana P
DP
English
Joyce
J
Varughese
Sara
S
Gasparrini
Ileana
I
Bortolomai
Natalia
N
Buza
Pei
P
Hui
Maysa
M
Abu-Khalaf
Antonella
A
Ravaggi
Eliana
E
Bignotti
Elisabetta
E
Bandiera
Chiara
C
Romani
Paola
P
Todeschini
Renata
R
Tassi
Laura
L
Zanotti
Luisa
L
Carrara
Sergio
S
Pecorelli
Dan-Arin
DA
Silasi
Elena
E
Ratner
Masoud
M
Azodi
Peter E
PE
Schwartz
Thomas J
TJ
Rutherford
Amy L
AL
Stiegler
Shrikant
S
Mane
Titus J
TJ
Boggon
Joseph
J
Schlessinger
Richard P
RP
Lifton
Alessandro D
AD
Santin
D000595:Amino Acid Sequence; D000818:Animals; D020137:Base Pair Mismatch; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D014594:Uterine Neoplasms / Q000235:genetics*