Mutation analysis of the <i>BRCA1</i> gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation

Matsushima, Mieko; Kobayashi, Kazutoyo; Emi, Mitsuru; Saito, Hiroko; Saito, Junko; Suzumori, Kaoru; Nakamura, Yusuke

doi:10.1093/hmg/4.10.1953

Cited by 82 publications

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“…The average age of onset for breast and ovarian cancer in Japanese patients with constitutional BRCA1 mutation was 51.8 years, that in patients carrying missense mutations was 50.2, and that in patients carrying nonsense or frameshift mutations was 52.7, as reported previously (Matsushima et al 1995;Inoue et al 1995;Katagiri et al 1996b). The results in this study are similar to the previous data and indicate that the average of age of onset for breast cancer in Japanese patients with constitutional BRCA1 or BRCA2 muta- tions was much later than in the case of predisposed patients in the United States or western Europe (Kelsey and Berkowitz 1988).…”

Section: Discussionsupporting

confidence: 82%

High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families

et al. 1998

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Mutations in either of two recently identified genes, BRCA1 and BRCA2, are thought to be responsible for approximately two-thirds of all cases of autosomaldominantly inherited breast cancer. To examine the nature and frequency of BRCA1 and BRCA2 mutations in Japanese families exhibiting a high incidence of breast cancer, we screened 78 unrelated families in this category for mutations of these two genes. Examining the entire coding sequences as well as exon-intron boundaries of both genes by polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) and multiplex-SSCP analysis, we identified possible disease-causing alterations in BRCA1 among affected members of 15 families and in BRCA2 in another 14 families. In 15 of those 29 families, the affected individuals carried missense mutations, although most germline mutations reported worldwide have been deletions or nonsense mutations. Our results, indicating that missense mutations of BRCA1 and BRCA2 tend to predominate over frameshifts or nonsense mutations in Japanese breast cancer families, will contribute significantly to an understanding of mammary tumorigenesis in Japan, and will be of vital importance for future genetic testing. pattern of inheritance of breast cancer were evaluated. For each family, a pedigree was prepared on the basis of a family member known to be affected. Key wordsOccurrence of cancer within each pedigree was confirmed by obtaining medical records and pathology reports for all available family members whether living or deceased. The criteria for selecting "breast cancer families" for this study were as follows: (a) at least three first-degree family members with breast cancer or (b) two or more first-degree family members with breast cancer, either early-onset, bilateral, or accompanied by a history of primary cancer(s) of other organs. Blood samples were obtained from affected family members through the aforementioned Societies. Genomic DNAs were extracted from fresh blood under standard protocols (Kunkel et al. 1977). Mutation screening SSCP-analysis.The entire coding sequences of BRCA1 and BRCA2, and associated exon-intron boundary sequences, were examined by PCR-SSCP analysis. The PCR primers used for PCR-SSCP analysis have been described elsewhere (Katagiri et al. 1996b, Miki et al. 1996.Each genomic DNA (50␣ ng) was amplified in a reaction mixture containing 10 ml of 1 ϫ PCR buffer (25␣ mM TAPS, 50␣ mM KCl, 2␣ mM MgCl 2 , and 1␣ mM β-mercaptoethanol), 20␣ mM dNTPs, 5␣ pmol primers, 2␣ mCi of α[ 32 P]dCTP (3000␣ Ci/mmol, 10␣ mCi/ml), and 0.5 units of Taq polymerase (Boehringer Mannheim, Mannheim, Germany). PCR conditions were 1 cycle at 94°C for 2␣ min, then 30 cycles at 94°C for 30␣ s, 60°C for 30␣ s, and 72°C for 30␣ s with final elongation at 72°C for 5␣ min. Each reaction mixture was diluted with 50␣ ml of 95% formamide dye and 20␣ mM ethylenediaminetetraacetic acid (EDTA), incubated at 85°C for 5␣ min, and electrophoresed in a 6% polyacrylamide gel containing 5% glycerol and 0.5 ϫ 90␣ mM Trisborat...

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Section: Discussionsupporting

confidence: 82%

High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families

et al. 1998

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“…The lifetime risk of developing ovarian cancer in BRCA1 and BRCA2 carriers is 28-44% [1,2,6,7]. Estimates of the frequency of BRCA1 and BRCA2 germline mutations in ovarian cancer patients have ranged between 2-12% and 2-6% for BRCA1 and BRCA2 mutations, respectively [2,3,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Improved survival in BRCA2 carriers with ovarian cancer

et al. 2006

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Objectives-The objective of this study was to investigate survival of ovarian cancer patients with BRCA1 and BRCA2 mutations compared to those without mutations in a population-based sample of incident epithelial ovarian cancer cases. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript the two analyses were similar, thus data involving the 209 invasive epithelial cancer cases are presented, as this was judged to be more clinically relevant. NIH Public AccessResults-In the multivariate analysis, BRCA status and stage were statistically significant, and were adjusted for in the survival analysis model. The Kaplan-Meier method estimated expected survival at 4 years of 83% of BRCA2 carriers compared to 37% of BRCA1 carriers and 12% of non-carriers. There was a statistically significant difference between BRCA2 carriers and noncarriers (p = 0.013). No statistically significant survival differences were seen for BRCA1 carriers when compared with either BRCA2 carriers or non-carriers.Conclusion-These data suggest that BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers. The etiology of this possible survival advantage is currently unknown. Larger studies are needed to confirm these results and to clarify their etiology and clinical significance.

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“…However, very few mutations have been found in sporadic ovarian cancer and, to date, there have been no somatic mutations described in breast cancers Merajver et al, 1995;Matsushima et al, 1995). Two clues as to its possible function lie in regions of homology to the family of zinc ®nger transcription factor proteins and to the secreted granin proteins , but the speci®c role of the gene remains unknown.…”

Section: Introductionmentioning

confidence: 99%

BRCA1 expression is not directly responsive to estrogen

et al. 1997

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Expression of the breast cancer susceptibility gene, BRCA1, is induced by 17-b estradiol (E 2 ) in estrogen receptor containing breast cancer cell lines. Our previous studies have shown that BRCA1 transcription is also regulated with the cell cycle, reaching maximal levels just before the onset of DNA synthesis. In this study, we have examined whether the estrogen induction of BRCA1 is direct or is a result of the mitogenic activity of the hormone. Four lines of evidence lead us to conclude that E 2 induces BRCA1 primarily through an increase in DNA synthesis: (1) The kinetics and magnitude of induction are di erent from the directly E 2 inducible gene, pS2; (2) Induction of BRCA1, but not pS2, is blocked by cycloheximide indicating that de novo protein synthesis is required; (3) Other hormonal and growth factor treatments that induce DNA synthesis have a similar e ect, including IGF-1, EGF and DNA synthetic ares induced by tamoxifen and retinoic acid; (4) BRCA1 genomic fragments near the 5' end of the gene containing putative estrogen response elements fail to respond to E 2 when transfected into breast cancer cell lines. The most consistent explanation for these ®ndings and other published studies is that BRCA1 transcription is induced as a result of the mitogenic activity of E 2 in estrogen receptor positive cells.

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Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation

Cited by 82 publications

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High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families

High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families

Improved survival in BRCA2 carriers with ovarian cancer

BRCA1 expression is not directly responsive to estrogen

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