Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer

Tanja Pejovic, Jane E. Yates, HongYan Liu, Laura E. Hays, Yassmine Akkari, Yumi Torimaru, Winifred Keeble, R. Keaney Rathbun, William H. Rodgers, Allen E. Bale, Najim Ameziane, C. Michael Zwaan, Abdellatif Errami, Philippe Thuillier, Fabio Cappuccini, Susan B. Olson, Joanna M. Cain, Grover C. Bagby

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.

Original languageEnglish (US)
Pages (from-to)9017-9025
Number of pages9
JournalCancer Research
Volume66
Issue number18
DOIs
StatePublished - Sep 15 2006

Fingerprint

Cytogenetics
Ovarian Neoplasms
Epithelial Cells
Mitomycin
Fanconi Anemia
Chromosome Breakage
Hypersensitivity
Mutation
Fanconi Anemia Complementation Group D2 Protein
Fanconi Anemia Complementation Group Proteins
Germ-Line Mutation
Genetic Promoter Regions
Methylation
Genes
Ovary
Complementary DNA
Lymphocytes
Breast Neoplasms
Carcinoma
Control Groups

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pejovic, T., Yates, J. E., Liu, H., Hays, L. E., Akkari, Y., Torimaru, Y., ... Bagby, G. C. (2006). Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. Cancer Research, 66(18), 9017-9025. https://doi.org/10.1158/0008-5472.CAN-06-0222

Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. / Pejovic, Tanja; Yates, Jane E.; Liu, HongYan; Hays, Laura E.; Akkari, Yassmine; Torimaru, Yumi; Keeble, Winifred; Rathbun, R. Keaney; Rodgers, William H.; Bale, Allen E.; Ameziane, Najim; Zwaan, C. Michael; Errami, Abdellatif; Thuillier, Philippe; Cappuccini, Fabio; Olson, Susan B.; Cain, Joanna M.; Bagby, Grover C.

In: Cancer Research, Vol. 66, No. 18, 15.09.2006, p. 9017-9025.

Research output: Contribution to journalArticle

Pejovic, T, Yates, JE, Liu, H, Hays, LE, Akkari, Y, Torimaru, Y, Keeble, W, Rathbun, RK, Rodgers, WH, Bale, AE, Ameziane, N, Zwaan, CM, Errami, A, Thuillier, P, Cappuccini, F, Olson, SB, Cain, JM & Bagby, GC 2006, 'Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer', Cancer Research, vol. 66, no. 18, pp. 9017-9025. https://doi.org/10.1158/0008-5472.CAN-06-0222
Pejovic T, Yates JE, Liu H, Hays LE, Akkari Y, Torimaru Y et al. Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. Cancer Research. 2006 Sep 15;66(18):9017-9025. https://doi.org/10.1158/0008-5472.CAN-06-0222
Pejovic, Tanja ; Yates, Jane E. ; Liu, HongYan ; Hays, Laura E. ; Akkari, Yassmine ; Torimaru, Yumi ; Keeble, Winifred ; Rathbun, R. Keaney ; Rodgers, William H. ; Bale, Allen E. ; Ameziane, Najim ; Zwaan, C. Michael ; Errami, Abdellatif ; Thuillier, Philippe ; Cappuccini, Fabio ; Olson, Susan B. ; Cain, Joanna M. ; Bagby, Grover C. / Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. In: Cancer Research. 2006 ; Vol. 66, No. 18. pp. 9017-9025.
@article{120f256ea9fc4dcabe8bfb53b8294c30,
title = "Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer",
abstract = "Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.",
author = "Tanja Pejovic and Yates, {Jane E.} and HongYan Liu and Hays, {Laura E.} and Yassmine Akkari and Yumi Torimaru and Winifred Keeble and Rathbun, {R. Keaney} and Rodgers, {William H.} and Bale, {Allen E.} and Najim Ameziane and Zwaan, {C. Michael} and Abdellatif Errami and Philippe Thuillier and Fabio Cappuccini and Olson, {Susan B.} and Cain, {Joanna M.} and Bagby, {Grover C.}",
year = "2006",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-06-0222",
language = "English (US)",
volume = "66",
pages = "9017--9025",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer

AU - Pejovic, Tanja

AU - Yates, Jane E.

AU - Liu, HongYan

AU - Hays, Laura E.

AU - Akkari, Yassmine

AU - Torimaru, Yumi

AU - Keeble, Winifred

AU - Rathbun, R. Keaney

AU - Rodgers, William H.

AU - Bale, Allen E.

AU - Ameziane, Najim

AU - Zwaan, C. Michael

AU - Errami, Abdellatif

AU - Thuillier, Philippe

AU - Cappuccini, Fabio

AU - Olson, Susan B.

AU - Cain, Joanna M.

AU - Bagby, Grover C.

PY - 2006/9/15

Y1 - 2006/9/15

N2 - Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.

AB - Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.

UR - http://www.scopus.com/inward/record.url?scp=33749465890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749465890&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-0222

DO - 10.1158/0008-5472.CAN-06-0222

M3 - Article

VL - 66

SP - 9017

EP - 9025

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 18

ER -