title: Emergence, involution, and progression to carcinoma of mutant clones in normal endometrial tissues.
abstract: Sporadic somatic inactivation of genes such as PTEN within histologically normal endometrium (latent precancers) is an early step in endometrial carcinogenesis. We have used clone-specific mutations of PTEN to determine the fate of latent precancers over time in women who do (high risk) and do not (low risk) develop endometrial neoplasia. PTEN immunohistochemistry was performed on 45 occurrences of endometrial neoplasia and their paired antecedent benign biopsies, along with age matched sample pairs from 167 patients who did not develop a neoplasm. When PTEN-deficient cells were present at both time points, DNA sequencing was performed to determine whether they were single or multiple independent events. Loss of PTEN protein in isolated glands was common in the initial normal biopsies of high- and low-risk groups (42% and 27%, respectively, P = 0.066). Protein-deficient glands have a tendency to disappear over time in low-risk women (P = 0.047) and, even when "persistent," are infrequently (19%, 3/16) confirmed to be the same clone. Similarly, only a small proportion (6.7%, 1/15) of latent precancers seen in high-risk women are the direct progenitors of subsequent neoplasia. There is a high rate of latent precancer turnover in both low- and high-risk patients, with rare long-term persistence of unique clones, which may or may not progress to a histologic lesion. The temporal dynamics of clonal emergence, persistence, and involution are sufficiently complex that in the individual patient, the presence of a latent precancer has an unknown contribution to long-term cancer risk.
authors.affiliation: Authors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio gmutter@partners.org.
authors.forename: George L
authors.initials: GL
authors.lastname: Mutter
authors.affiliation: Authors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Monte
authors.affiliation: Authors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Authors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Alex
authors.initials: A
authors.lastname: Ferenczy
authors.affiliation: Authors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OhioAuthors' Affiliations: Department of Pathology at Brigham and Women's Hospital; Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts; Departments of Pathology, McGill University and the Jewish General Hospital, Montreal, Canada; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic; and Department of Genetics and Genome Sciences, and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004717:Endometrium / Q000201:enzymology / Q000473:pathology* / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D012307:Risk Factors
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human