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Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression.
Gynecol Oncol. 2019 01; 152(1):11-19.GO

Abstract

OBJECTIVE

Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs.

METHODS

Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data.

RESULTS

POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p < 0.001) or basal-like breast cancers (46%, p < 0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases.

CONCLUSIONS

The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.

Authors+Show Affiliations

Department of Surgery, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Surgery, Gynecology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: weigeltb@mskcc.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30415991

Citation

Ashley, Charles W., et al. "Analysis of Mutational Signatures in Primary and Metastatic Endometrial Cancer Reveals Distinct Patterns of DNA Repair Defects and Shifts During Tumor Progression." Gynecologic Oncology, vol. 152, no. 1, 2019, pp. 11-19.
Ashley CW, Da Cruz Paula A, Kumar R, et al. Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. Gynecol Oncol. 2019;152(1):11-19.
Ashley, C. W., Da Cruz Paula, A., Kumar, R., Mandelker, D., Pei, X., Riaz, N., Reis-Filho, J. S., & Weigelt, B. (2019). Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. Gynecologic Oncology, 152(1), 11-19. https://doi.org/10.1016/j.ygyno.2018.10.032
Ashley CW, et al. Analysis of Mutational Signatures in Primary and Metastatic Endometrial Cancer Reveals Distinct Patterns of DNA Repair Defects and Shifts During Tumor Progression. Gynecol Oncol. 2019;152(1):11-19. PubMed PMID: 30415991.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression. AU - Ashley,Charles W, AU - Da Cruz Paula,Arnaud, AU - Kumar,Rahul, AU - Mandelker,Diana, AU - Pei,Xin, AU - Riaz,Nadeem, AU - Reis-Filho,Jorge S, AU - Weigelt,Britta, Y1 - 2018/11/08/ PY - 2018/08/30/received PY - 2018/10/22/revised PY - 2018/10/23/accepted PY - 2018/11/13/pubmed PY - 2019/2/5/medline PY - 2018/11/13/entrez KW - Carcinosarcoma KW - Endometrial cancer KW - Metastasis KW - Molecular subtypes KW - Mutational signatures SP - 11 EP - 19 JF - Gynecologic oncology JO - Gynecol Oncol VL - 152 IS - 1 N2 - OBJECTIVE: Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. METHODS: Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. RESULTS: POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p < 0.001) or basal-like breast cancers (46%, p < 0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. CONCLUSIONS: The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies. SN - 1095-6859 UR - https://www.unboundmedicine.com/medline/citation/30415991/Analysis_of_mutational_signatures_in_primary_and_metastatic_endometrial_cancer_reveals_distinct_patterns_of_DNA_repair_defects_and_shifts_during_tumor_progression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(18)31316-7 DB - PRIME DP - Unbound Medicine ER -