Use of mutation profiles to refine the classification of endometrial carcinomas.
The classification of endometrial carcinomas is based on pathological assessment of tumour cell type; the different cell types (endometrioid, serous, carcinosarcoma, mixed, undifferentiated, and clear cell) are associated with distinct molecular alterations. This current classification system for high-grade subtypes, in particular the distinction between high-grade endometrioid (EEC-3) and serous carcinomas (ESC), is limited in its reproducibility and prognostic abilities. Therefore, a search for specific molecular classifiers to improve endometrial carcinoma subclassification is warranted. We performed target enrichment sequencing on 393 endometrial carcinomas from two large cohorts, sequencing exons from the following nine genes: ARID1A, PPP2R1A, PTEN, PIK3CA, KRAS, CTNNB1, TP53, BRAF, and PPP2R5C. Based on this gene panel, each endometrial carcinoma subtype shows a distinct mutation profile. EEC-3s have significantly different frequencies of PTEN and TP53 mutations when compared to low-grade endometrioid carcinomas. ESCs and EEC-3s are distinct subtypes with significantly different frequencies of mutations in PTEN, ARID1A, PPP2R1A, TP53, and CTNNB1. From the mutation profiles, we were able to identify subtype outliers, ie cases diagnosed morphologically as one subtype but with a mutation profile suggestive of a different subtype. Careful review of these diagnostically challenging cases suggested that the original morphological classification was incorrect in most instances. The molecular profile of carcinosarcomas suggests two distinct mutation profiles for these tumours: endometrioid-type (PTEN, PIK3CA, ARID1A, KRAS mutations) and serous-type (TP53 and PPP2R1A mutations). While this nine-gene panel does not allow for a purely molecularly based classification of endometrial carcinoma, it may prove useful as an adjunct to morphological classification and serve as an aid in the classification of problematic cases. If used in practice, it may lead to improved diagnostic reproducibility and may also serve to stratify patients for targeted therapeutics.
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Melissa K
MK
McConechy
Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.|Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.
Jiarui
J
Ding
Department of Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada.
Maggie Cu
MC
Cheang
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Kimberly
K
Wiegand
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Janine
J
Senz
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Alicia
A
Tone
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Winnie
W
Yang
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.
Leah
L
Prentice
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
Kane
K
Tse
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
Thomas
T
Zeng
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
Helen
H
McDonald
Department of Surgery, Siteman Cancer Center and Washington University School of Medicine, St. Louis, Missouri, USA.
Amy P
AP
Schmidt
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center and Washington University School of Medicine, St. Louis, Missouri, USA.
David G
DG
Mutch
Division of Gynaecologic Oncology, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada.
Jessica N
JN
McAlpine
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Microbiology and Immunology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada.
Martin
M
Hirst
Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.|Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.
Sohrab P
SP
Shah
Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
Cheng-Han
CH
Lee
Department of Surgery, Siteman Cancer Center and Washington University School of Medicine, St. Louis, Missouri, USA.
Paul J
PJ
Goodfellow
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
C Blake
CB
Gilks
Department of Pathology and Laboratory Medicine, University of British Columbia, BC Cancer Agency, Vancouver, BC, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver, BC, Canada.
David G
DG
Huntsman
D018269:Carcinoma, Endometrioid / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D002296:Carcinosarcoma / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D016889:Endometrial Neoplasms / Q000145:classification* / Q000175:diagnosis / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D053842:Microsatellite Instability; D009154:Mutation; D009857:Oncogenes; D015398:Signal Transduction
D004273:DNA, Neoplasm