Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression

被引：70

作者：

Ashley, Charles W. ^{[1
]}

Paula, Arnaud Da Cruz ^{[1
]}

Kumar, Rahul ^{[2
]}

Mandelker, Diana ^{[2
]}

Pei, Xin ^{[3
]}

Riaz, Nadeem ^{[3
]}

Reis-Filho, Jorge S. ^{[2
]}

Weigelt, Britta ^{[2
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

来源：

GYNECOLOGIC ONCOLOGY | 2019年 / 152卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Endometrial cancer; Carcinosarcoma; Mutational signatures; Metastasis; Molecular subtypes; MOLECULAR CLASSIFICATION; BREAST-CANCER; DEFICIENCIES; DEFINES;

D O I：

10.1016/j.ygyno.2018.10.032

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 deconstnictSigs, 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 (serouslike) 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. (C) 2018 Published by Elsevier Inc.

引用

页码：11 / 19

页数：9

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