Loss of heterozygosity of BRCA1, TP53 and TCRD markers analysed in sporadic endometrial cancer

Niederacher, Dieter; An, Han‐Xiang; Camrath, Stefan; Dominik, S.; Göhring, Uwe-Jochen; Oertel, Anne; M, Grass; Hantschmann, Peer; Lordnejad, Mohammad Reza; Beckmann, Matthias W.

doi:10.1016/s0959-8049(98)00270-6

Cited by 18 publications

(22 citation statements)

References 29 publications

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“…The role of BRCA1 in endometrial carcinoma has been investigated; however, different studies reached different conclusions. Niederacher et al (38) examined 113 archival endometrial cancer samples and found that 18.1% carried BRCA1 mutations. Moreover, loss of heterozygosity of BRCA1 correlated significantly with a decreased overall survival rate of patients (38).…”

Section: Discussionmentioning

confidence: 99%

“…Niederacher et al (38) examined 113 archival endometrial cancer samples and found that 18.1% carried BRCA1 mutations. Moreover, loss of heterozygosity of BRCA1 correlated significantly with a decreased overall survival rate of patients (38). In contrast, Levine et al (29) investigated 199 Ashkenazi Jewish patients with endometrial cancers by screening three BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) and found that only 3 of the 199 patients (1.5%) had BRCA1 or BRCA2 mutations (29).…”

Section: Discussionmentioning

confidence: 99%

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Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

Kim

Cao

et al. 2004

Molecular and Cellular Biology

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The tumor suppressor BRCA1 contains multiple functional domains that interact with many proteins. After DNA damage, BRCA1 is phosphorylated by CHK2 at serine 988, followed by a change in its intracellular location. To study the functions of CHK2-dependent phosphorylation of BRCA1, we generated a mouse model carrying the mutation S971A (S971 in mouse Brca1 corresponds to S988 in human BRCA1) by gene targeting. Brca1S971A/S971A mice were born at the expected ratio without a developmental defect, unlike previously reported Brca1 mutant mice. However, Brca1 S971A/S971A mice suffered a moderately increased risk of spontaneous tumor formation, with a majority of females developing uterus hyperplasia and ovarian abnormalities by 2 years of age. After treatment with DNA-damaging agents, Brca1 S971A/S971A mice exhibited several abnormalities, including increased body weight, abnormal hair growth pattern, lymphoma, mammary tumors, and endometrial tumors. In addition, the onset of tumor formation became accelerated, and 80% of the mutant mice had developed tumors by 1 year of age. We demonstrated that the Brca1 S971A/S971A cells displayed reduced ability to activate the G 2 /M cell cycle checkpoint upon ␥-irradiation and to stabilize p53 following N-methyl-N-nitro-N-nitrosoguanidine treatment. These observations suggest that Chk2 phosphorylation of S971 is involved in Brca1 function in modulating the DNA damage response and repressing tumor formation.Germ line mutations of BRCA1 predispose women to breast cancer and ovarian cancer (1, 7). Although the specific molecular events leading to tumorigenesis remain elusive, several lines of evidence indicate that BRCA1 is involved in genetic stability control, DNA damage repair, centrosome duplication, apoptosis, and cell cycle control (reviewed in references 13, 16, 48, and 56). BRCA1 functions are mediated by several different mechanisms, including phosphorylation. It has been shown that BRCA1 undergoes hyperphosphorylation during late G 1 and S phases and is transiently dephosphorylated soon after M phase (42,47).During the DNA damage response, BRCA1 is phosphorylated by several protein kinases, such as ATM, ATR, CHK1, CHK2, and MDC1 (10, 31, 58). ATM controls cell cycle arrest in G 1 and G 2 . The control mechanism of G 2 arrest by ATM is unclear, but recently CHK2, the mammalian homolog of the budding yeast Rad53 and fission yeast Cds1 checkpoint kinases, was cloned and found to be linked to ATM: in response to ionizing radiation (IR), CHK2 is rapidly phosphorylated and activated in an ATM-dependent manner (18,21,33). In Chk2 mutant mouse embryonic stem (ES) cells, maintenance of G 2 arrest and reduced Cdc2 kinase activity in response to IR are defective (24).The first evidence that CHK2 acts as a tumor suppressor came from a finding that a subset of patients with Li-Fraumeni syndrome, which is characterized by multiple tumors at an early age, contained germ line mutations in CHK2 (5). Somatic mutations of CHK2 have also been found in diverse types of sporadic cancer, includ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

Kim

Cao

et al. 2004

Molecular and Cellular Biology

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“…In contrast to Cyber-T and SAM, ICA identified a significantly higher number of genes on chromosome 17 than would be expected from the overall chromosomal distribution of genes on the array. More specifically, of the genes identified by ICA, 10 hits were from genes mapping to cytoband 17q21, a locus which has previously been shown to exhibit loss of heterozygosity in endometrial cancer (Niederacher et al, 1999;Sirchia et al, 2000). Cyber-T and SAM, however, identified only six and two gene hits, respectively, at the 17q21 locus.…”

Section: Ica Identified Novel Patterns Of Coregulated Genes Clinicallmentioning

confidence: 99%

Independent component analysis of microarray data in the study of endometrial cancer

et al. 2004

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“…ras mutations have been detected in 10% of simple, 14% of complex, and Gurpide 1991, Jeyarajah et al 1996a, Terakawa et al 1996, Niederacher et al 1998, Reynolds et al 1998, Niederacher et al 1999, Quinn 1999, Sherman 2000. …”

Section: Mismatch Repair Defectsmentioning

confidence: 99%

Hormonal interactions in endometrial cancer.

Emons

Fleckenstein

Hinney³

et al. 2000

Endocrine-Related Cancer

172

129

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Endometrial cancer (EC) is the most frequent malignant tumor of the female genital tract. Increasing evidence suggests that at least two different types of EC exist. Type I is associated with an endocrine milieu of estrogen predominance. These tumors are of endometrioid histology and develop from endometrial hyperplasia. They have a good prognosis and are sensitive to endocrine manipulation. Type II EC is not associated with a history of unopposed estrogens and develops from the atrophic endometrium of elderly women. They are of serous histology, have a poor prognosis, and do not react to endocrine manipulation. Both types of EC probably differ markedly with regard to the molecular mechanisms of malignant transformation. This article reviews reproductive and lifestyle factors modifying the risk of developing type I EC, including the use of hormonal contraceptives, hormone replacement therapy and tamoxifen. The roles of established and novel therapies for precancerous lesions and for invasive EC in the adjuvant and palliative settings are discussed.

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Loss of heterozygosity of BRCA1, TP53 and TCRD markers analysed in sporadic endometrial cancer

Cited by 18 publications

References 29 publications

Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

Uterus Hyperplasia and Increased Carcinogen-Induced Tumorigenesis in Mice Carrying a Targeted Mutation of the Chk2 Phosphorylation Site in Brca1

Independent component analysis of microarray data in the study of endometrial cancer

Hormonal interactions in endometrial cancer.

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