title: The Li-Fraumeni syndrome (LFS): a model for the initiation of p53 signatures in the distal Fallopian tube.
abstract: A candidate early precursor to pelvic serous cancer, the 'p53 signature', is commonly found in the benign mucosa of the distal Fallopian tube and harbours p53 mutations and evidence of DNA damage. We examined tubes from women with pre-existing (germ-line) mutations in p53 [Li-Fraumeni syndrome (LFS)] for evidence of this precursor. Fallopian tubes from two cases of LFS were immunostained for p53, Ki-67 (proliferation) and H2AX (DNA damage response) and analysed for p53 mutations by laser capture microdissection (LCM) and p53 genomic sequencing (exons 2-11). A common single nucleotide repeat (snp) in exon 3 (rs1042522) and deletion sequencing chromatograms in exon 4 were examined in combination to estimate LOH in both LFS tubes and advanced serous carcinomas from the general population. LFS tubal epithelium contained abundant (10-20 per section) p53 signatures with evidence of DNA damage and low proliferative activity. Six of 11 LFS microdissected p53 signatures (55%) and 15 of 21 serous carcinomas (71%) revealed LOH at the p53 locus, relative to background epithelium. The LFS model confirms prior observations that the distal Fallopian tube is particularly prone to focal epithelial p53 gene inactivation-p53 mutation and LOH-in the absence of malignancy or increased epithelial proliferation. The fact that the LFS is not associated with ovarian cancers is consistent with the concept that loss of p53 function must be accompanied by at least one more genotoxic event (including BRCA1/2 functional inactivation) to produce the malignant phenotype. This is in keeping with a general model of carcinogenesis, in which different and often independent risk factors operate at multiple points in the serous carcinogenic spectrum.
authors.affiliation: Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Wa
authors.initials: W
authors.lastname: Xian
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Michael
authors.initials: M
authors.lastname: Roh
authors.forename: Dana R
authors.initials: DR
authors.lastname: Semmel
authors.forename: Yosuf
authors.initials: Y
authors.lastname: Yassin
authors.forename: Judy
authors.initials: J
authors.lastname: Garber
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.forename: Annekathryn
authors.initials: A
authors.lastname: Goodman
authors.forename: Karishma
authors.initials: K
authors.lastname: Mehra
authors.forename: Ross S
authors.initials: RS
authors.lastname: Berkowitz
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Quade
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004252:DNA Mutational Analysis / Q000379:methods; D005185:Fallopian Tube Neoplasms / Q000235:genetics / Q000378:metabolism; D005187:Fallopian Tubes / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D016130:Immunophenotyping; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism*; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53