TY - JOUR
T1 - Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas
AU - Liu, Yihua
AU - Weber, Zachary
AU - San Lucas, F. Anthony
AU - Deshpande, Aditya
AU - Jakubek, Yasminka A.
AU - Sulaiman, Raed
AU - Fagerness, Mary
AU - Flier, Natasha
AU - Sulaiman, Joseph
AU - Davis, Christel M.
AU - Fowler, Jerry
AU - Starks, David
AU - Rojas-Espaillat, Luis
AU - Lazar, Alexander J.
AU - Davies, Gareth E.
AU - Ehli, Erik A.
AU - Scheet, Paul
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/11
Y1 - 2018/11
N2 - Objective: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. Methods: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. Results: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. Conclusions: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.
AB - Objective: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. Methods: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. Results: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. Conclusions: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.
KW - Biphasic
KW - Carcinosarcoma
KW - Genomics
KW - Haplotype
KW - Heterogeneity
KW - Uterine cancer
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U2 - 10.1016/j.ygyno.2018.08.043
DO - 10.1016/j.ygyno.2018.08.043
M3 - Article
C2 - 30194005
AN - SCOPUS:85052844083
SN - 0090-8258
VL - 151
SP - 243
EP - 249
JO - Gynecologic oncology
JF - Gynecologic oncology
IS - 2
ER -