Jungyoon Choi1, Andreana N Holowatyj1, Mengmeng Du2, Zhishan Chen1, Wanqing Wen1, Nikolaus Schultz2, Loren Lipworth1, Xingyi Guo1,3. 1. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN. 2. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. 3. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.
Abstract
PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.
PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.
Authors: M L Cote; J J Ruterbusch; Q Ahmed; S Bandyopadhyay; B Alosh; E Abdulfatah; S Seward; R Morris; R Ali-Fehmi Journal: Gynecol Oncol Date: 2014-04 Impact factor: 5.482
Authors: Tara E Soumerai; Mark T A Donoghue; Barry S Taylor; David M Hyman; Chaitanya Bandlamudi; Preethi Srinivasan; Matthew T Chang; Dmitriy Zamarin; Karen A Cadoo; Rachel N Grisham; Roisin E O'Cearbhaill; William P Tew; Jason A Konner; Martee L Hensley; Vicky Makker; Paul Sabbatini; David R Spriggs; Tiffany A Troso-Sandoval; Alexandra Snyder Charen; Claire Friedman; Mila Gorsky; Sarah J Schweber; Sumit Middha; Rajmohan Murali; Sarah Chiang; Kay J Park; Robert A Soslow; Marc Ladanyi; Bob T Li; Jennifer Mueller; Britta Weigelt; Ahmet Zehir; Michael F Berger; Nadeem R Abu-Rustum; Carol Aghajanian; Deborah F DeLair; David B Solit Journal: Clin Cancer Res Date: 2018-08-01 Impact factor: 12.531
Authors: N Colombo; C Creutzberg; F Amant; T Bosse; A González-Martín; J Ledermann; C Marth; R Nout; D Querleu; M R Mirza; C Sessa Journal: Ann Oncol Date: 2015-12-02 Impact factor: 32.976