Abstract
Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Body Mass Index
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Class I Phosphatidylinositol 3-Kinases
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Cohort Studies
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Endometrial Neoplasms / diagnosis
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Endometrial Neoplasms / genetics*
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Endometrial Neoplasms / metabolism*
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Exome / genetics
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Female
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Gene Expression Profiling / methods*
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Humans
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Immunohistochemistry
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In Situ Hybridization, Fluorescence
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Mutation
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Neoplasm Metastasis
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Obesity / complications*
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Oligonucleotide Array Sequence Analysis
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proteomics / methods*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras)
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sequence Analysis, DNA
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ras Proteins / genetics
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ras Proteins / metabolism
Substances
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Biomarkers, Tumor
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KRAS protein, human
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Proto-Oncogene Proteins
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RNA, Messenger
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Phosphatidylinositol 3-Kinases
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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PTEN Phosphohydrolase
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PTEN protein, human
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Proto-Oncogene Proteins p21(ras)
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ras Proteins