Supplementary Figure S2 from Genomic Landscapes of Endometrioid and Mucinous Ovarian Cancers and Morphologically Similar Tumor Types

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posted on 2025-11-05, 07:01 authored by Dorothy Hallberg, Alice C. Eastman, Shashikant Koul, Daniel C. Bruhm, Eniko Papp, Simon Davenport, Vilmos Adleff, Leonardo Ferreira, Noushin Niknafs, Jamie E. Medina, Stephen Cristiano, Carolyn Hruban, Jacob Fiksel, Kaui P. Lebarbenchon, Luis Aparicio, Nicholas A. Vulpescu, Kuan-Ting Kuo, Nita Ahuja, Ronny Drapkin, Euihye Jung, Sarah H. Kim, Mark A. Eckert, Ernst Lengyel, Kentaro Nakayama, Ayse Ayhan, Ie-Ming Shih, Tian-Li Wang, Ofer Lavie, Gad Rennert, Hariharan Easwaran, Stephen B. Baylin, Michael F. Press, Victor E. Velculescu, Robert B. Scharpf

<p>Mutations in ESR1 at Tyr537 and Leu536. ESR1 mutations identified in two patients with uterine endometrioid carcinomas occurred at Tyr537, a hotspot most commonly associated with aromatase inhibitor resistance in patients with breast cancer patients, and Leu536. This hotspot is in close proximity to the region of the estrogen receptor that is important for ligand-dependent transcriptional function. The Tyr537 mutations cause a conformational change that constitutively activates the receptor independent of estrogen receptor binding. The Tyr537 residue is highlighted in blue in a three-dimensional view of the ESR1 protein (bottom). Due to its physical proximity to the Tyr537 hotspot, the Leu536 mutation is likely to have the same activating effect on the estrogen receptor.</p>

Funding

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)

Gray Foundation

National Institutes of Health (NIH)

Commonwealth Foundation for Cancer Research Foundation

U.S. Department of Defense (DOD)

Honorable Tina Brozman Foundation (Tina’s Wish)

Stand Up To Cancer (SU2C)

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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DOI - Is supplement to Genomic Landscapes of Endometrioid and Mucinous Ovarian Cancers and Morphologically Similar Tumor Types

ARTICLE ABSTRACT

Endometrioid and mucinous ovarian carcinomas represent nearly a fifth of ovarian cancers, but their molecular characteristics and pathologic origins are poorly understood. To identify the genomic and epigenomic alterations characteristic of these ovarian cancer subtypes and evaluate links to morphologically similar tumors from other sites, we performed a combination of sequence, copy number, mutation signature, and rearrangement analyses from tumor samples and matched normal tissues of 133 patients, as well as methylation analyses of these tumors and tissues of 150 patients from The Cancer Genome Atlas. Genomic analyses included samples from patients with ovarian endometrioid (n = 44), ovarian mucinous (n = 43), uterine endometrioid (n = 15), and gastrointestinal mucinous carcinomas (n = 31), including mucinous carcinomas of the stomach, colon, and pancreas. In addition to identifying genes previously known to be involved in these tumors, we identified alterations in RAD51C, NOTCH4, SMARCA1/4, and JAK1 in ovarian endometrioid, ESR1 in uterine endometrioid, and SMARCA4 in ovarian mucinous carcinomas. Whole-genome sequencing revealed rearrangements involving PTEN, NF1, and NF2 in ovarian endometrioid carcinomas and NF1 and MED1 in ovarian mucinous carcinomas. The number of alterations, affected genes, and genome-wide methylation profiles were not distinguishable between ovarian and uterine endometrioid carcinomas, supporting the hypothesis that these tumors share a tissue of origin. In contrast, mutation and methylation patterns in ovarian mucinous carcinomas were different from gastrointestinal mucinous carcinomas. These analyses provide insights into the genomic landscapes and origins of mucinous and endometrioid ovarian carcinomas, providing new avenues for early clinical intervention and management of patients with these cancers. Integrative multi-omic analyses support a common tissue of origin between ovarian endometrioid and uterine endometrioid carcinomas but not between ovarian mucinous and gastric or pancreatic mucinous carcinomas.