Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ishitobi, M.
Right arrow Articles by Noguchi, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ishitobi, M.
Right arrow Articles by Noguchi, S.
Clinical Cancer Research Vol. 9, 1376-1380, April 2003
© 2003 American Association for Cancer Research

Molecular Oncology,Markers,Clinical Correlates

Association of BRCA2 Polymorphism at Codon 784 (Met/Val) with Breast Cancer Risk and Prognosis1

Makoto Ishitobi, Yasuo Miyoshi, Akiko Ando, Seiichi Hasegawa, Chiyomi Egawa, Yasuhiro Tamaki, Morito Monden and Shinzaburo Noguchi2

Departments of Surgical Oncology [M. I., Y. M., A. A., C. E., Y. T., S. N.] and Surgery and Clinical Oncology [S. H., M. M.], Osaka University Graduate School of Medicine, Osaka 565-0871, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] withbreast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients.

Experimental Design: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer.

Results: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07–3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status.

Conclusion: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent success in chemoprevention with tamoxifen seems to have opened the door for a new era when the prevention of breast cancer is emphasized much more than the treatment of established breast cancer. Currently, the United States Food and Drug Administration guidelines state that women ages 35 years and older, with a 5-year risk of breast cancer of 1.67% or greater are eligible for the prophylactic use of tamoxifen (1) . It is of pivotal importance to estimate the risk of breast cancer with a high precision to conduct chemoprevention efficiently. Breast cancer risk is usually estimated by the Gail model (2) , which is a well-established risk assessment model based on the epidemiological risk factors such as age, parity, family history, age at menarche, breast biopsy history, and race. Recently, a many studies have focused on the development of genetic polymorphisms that are associated with breast cancer risk independently of the epidemiological risk factors to assess the individual risk more precisely and to select the candidates for chemoprevention more efficiently (3) .

Thus far, a number of genetic polymorphisms of various genes have been studied in their association with breast cancer risk; these genes include mostly genes for steroid hormone biosynthesis and metabolism enzymes (CYP17, CYP19, COMT, and so forth) and carcinogen metabolism enzymes (GSTP1, CYP1A1, and so forth), and other genes (ER-{alpha}, PR, TP53, and so forth; Ref. 3 ). In addition, recently, genetic polymorphisms of BRCA1 and BRCA2 have been attracting a considerable attention because deleterious germ-line mutations in BRCA1 and BRCA2 confer a greatly increased risk of breast cancer (4) ; and, thus, common variants of these genes are expected to be ideal candidates for low penetrance alleles. Several genetic polymorphisms of BRCA1 and BRCA2 have been studied on their association with breast cancer risk, and it has been suggested that the genetic polymorphisms of BRCA1 [Glu (E)/Arg (R) 356 (5) and Leu (L)/Pro (P) 871 (6) ] and BRCA2 [Asn (N)/His (H) 372; Refs. 7 , 8 ] are significantly associated with breast cancer risk, although contradicting results have also been reported.

Recently, we have conducted the mutational analysis of BRCA1 and BRCA2 in Japanese breast cancer families (9) . During the study, we have identified several genetic polymorphisms in these genes, which include BRCA2 (N/H) at codon 372 and [Met (M)/Val (V)] at codon 784. In the present study, we have investigated the association of these polymorphisms with breast cancer risk in Japanese women by a case-control study. Furthermore, the prognostic significance of these polymorphisms was also studied.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cases and Controls.
Eligible cases (n = 149) were women who lived in Osaka, Japan, and underwent mastectomy or breast conserving surgery in the Osaka university hospital during the period of October 1998 to March 2001. They were consecutively recruited in this study. The histological diagnosis of breast cancer [ductal carcinoma in situ (n = 4), invasive ductal cancer (n = 130), invasive lobular carcinoma (n = 8), and other types of carcinoma (n = 7)] was confirmed in each case. Controls were women who lived in Osaka and participated in a mass screening program for breast cancer that was held in the affiliated institutes in Osaka. Women who were found to be free from breast cancer by physical examination and mammography were consecutively recruited as controls (n = 159) during the period of April 2001 to March 2002. Written informed consent was obtained from all participants.

Patient Prognosis.
The prognostic significance of BRCA2 polymorphisms at codon 372 and 784 was studied in 139 breast cancer patients (patients with ductal carcinoma in situ (n = 4) and those with distant metastases at the time of diagnosis (n = 6) were excluded from the analysis). Histological grading was done according to a method described previously (10) . Patients received a physical examination every 3 months for 2 years postoperatively and every 6 months thereafter. Chest X-ray and abdominal ultrasonogram were obtained every 6 months after the surgery. Three patients received no adjuvant therapy, 76 patients received endocrine therapy (tamoxifen, 5 years), 21 patients received chemotherapy (cyclophosphamide, methotrexate, and fluorouracil, 6 cycles), and 39 patients received chemoendocrine therapy, essentially according to the St. Gallen recommendations (11) . The median follow-up period was 24 months (range, 7–44 months), and the 3-year DFS3 was 87%. Fourteen of 139 patients developed recurrences: 1 developed brain metastasis, 2 developed lung metastases, 1 developed liver metastasis, 3 developed bone metastases, and 7 developed soft tissue metastases. Ipsilateral breast recurrences after breast-conserving surgery were not counted as recurrences.

DNA Isolation.
Mononuclear cells were isolated by Ficoll-Paque from the EDTA-treated peripheral blood samples obtained from the participants and were subjected to DNA extraction according to the phenol/chloroform method.

Genotyping.
The genotype of BRCA2 N/H372 polymorphism was determined using the ABI Prism 7700 Sequence Detection System (Applied Biosystems), as described by Healey et al. (7) .

The BRCA2 M/V784 polymorphism was detected using the PCR-SSCP method. PCR amplification was carried out in a total volume of 20 µl containing 25 ng of genomic DNA as a template using primers 5'-TGGAATACAGTGATACTGAC-3' and 5'-TTGGATTACTCTTAGATTTG-3'. The PCR reaction was carried out in a condition of a 5-min initial denaturation at 94°C followed by 35 cycles of amplification at 94°C for 30 s, 56°C for 30 s, and 72°C for 30 s, on the GeneAmp PCR system 9600 (Perkin-Elmer, Foster City, CA). Amplified samples were diluted 1:1 in loading buffer (95% formamide, 10 mM EDTA, and 0.25% bromphenol blue and xylene-cyanol), kept at 95°C for 5 min, and then cooled quickly on ice. For each sample, 3 µl were loaded onto a 5% polyacrylamide SSCP gel containing 10% glycerol and were run at 350–400V constant power for 15–17 h in 0.5x Tris-borate EDTA buffer (TBE) at 4°C. After electrophoresis, each band was visualized by staining with SYBR GREEN II (FMC Bioproducts, Rockland, ME) and was analyzed by the FMBIOII image analyzer (Takara, Kyoto, Japan). All of the variant bands detected were excised from the SSCP gel, reamplified, purified, and sequenced by an ABI Prism 310 automated sequencer (Perkin-Elmer).

ER Assay.
An enzyme immunoassay was conducted to measure ER protein levels in breast cancers using the kit provided by Abbott (Chicago, IL) according to the manufacturer’s instructions. The cutoff value for ER was 5 fmol/mg protein.

Statistical Analysis.
The association between the BRCA2 polymorphisms and breast cancer risk or clinicopathological parameters was assessed using the {chi}2 test. A logistic regression model was used to calculate the ORs and 95% CI of each genotype, being adjusted for the other epidemiological risk factors (age, family history, age at menarche, age at first birth, body mass index, breast biopsy history). DFS curves were calculated by the Kaplan-Meier method. The log-rank test was used to evaluate the differences in DFS among the various patient subgroups. A Cox proportional hazards model was used for multivariate analysis. All of the statistical tests and Ps were two-tailed and Ps of <0.05 were considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Relationship between BRCA2 Polymorphisms and Breast Cancer Risk.
The genotype of BRCA2 polymorphisms at codon 372 (N/H) and 784 (M/V) was determined in 149 cases and 154 controls. The representative results of SSCP analysis of the BRCA2 M/V784 polymorphism are shown in Fig. 1Citation . The N/H372 polymorphism was not significantly associated with breast cancer risk after adjustment for the various epidemiological risk factors (age, family history, age at menarche, age at first birth, body mass index, breast biopsy history).



View larger version (61K):
[in this window]
[in a new window]
  		Fig. 1. Representative results of SSCP analysis of BRCA2 polymorphism at codon 784 (M/V). Arrows, a band corresponding to the variant allele (V784). Lanes 1, 2, 4–8, and 10, genotype M/M; Lanes 3 and 9, genotype M/V.

 
The frequencies of M/M784 homozygotes and M/V784 heterozygotes were 79 and 21%, respectively, in cases and 87 and 13%, respectively, in controls. There was no V/V homozygote either in cases or controls. After adjustment for age, the variant allele carriers (M/V784) showed a marginally significant increase (OR, 1.78; P = 0.07) in the breast cancer risk as compared with the variant allele noncarriers (M/M784). After adjustment for the epidemiological risk factors, the variant allele carriers showed a significant increase (OR, 2.03; P = 0.03) in the breast cancer risk as compared with the variant allele noncarriers. Subset analysis according to the menopausal status showed a trend that the variant allele carriers had an increased risk of breast cancer both in premenopausals (OR, 2.22; P = 0.11) and postmenopausals (OR, 1.90; P = 0.17; Table 1Citation ).


View this table:
[in this window]
[in a new window]
  		Table 1 Associations between genotype of BRCA2 polymorphisms and breast cancer risk according to menopausal status

 
Relationship between BRCA2 Polymorphisms and Clinicopathological Parameters.
The relationship between BRCA2 polymorphisms and clinicopathological parameters of the breast cancers is shown in Table 2Citation . Neither BRCA2 polymorphisms (N/H372 nor M/V784) showed a significant association with any of the clinicopathological factors including menopausal status, tumor size, lymph node status, ER status, and histological grade.


View this table:
[in this window]
[in a new window]
  		Table 2 Relationship between genotype of BRCA2 polymorphisms and clinicopathological parameters

 
Prognosis and BRCA2 Polymorphisms.
Three-year DFS rates according to the various clinicopathological parameters are shown in Table 3Citation . Lymph node metastases and ER negativity were each significantly associated with poor prognosis (Table 3)Citation . In addition, variant allele carriers of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year DFS rate (63%) than noncarriers (92%; Table 3Citation ; Fig. 2Citation ). On the other hand, the N/H372 polymorphism was not significantly associated with patient prognosis.


View this table:
[in this window]
[in a new window]
  		Table 3 Three-year DFS rate (%) according to various prognostic factors

 


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 2. DFS rates of breast cancer patients according to BRCA2 polymorphism. A, BRCA2 N/H372 polymorphism. A1 allele (N372), A2 allele (H372). B, BRCA2 M/V784 polymorphism. A1 allele (M784), A2 allele (V784).

 
Prognostic significance of the M/V784 polymorphism was further analyzed by multivariate analysis to see its independence of the other prognostic factors (lymph node status and ER status; Table 4Citation ). Multivariate analysis has revealed that the M/V784 polymorphism is a significant and independent prognostic factor.


View this table:
[in this window]
[in a new window]
  		Table 4 Univariate and multivariate analysis of various prognostic factors

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we have been able to show that the BRCA2 M/V784 polymorphism, but not the N/H372 polymorphism, is significantly associated with breast cancer risk, i.e., the variant allele (V784) carriers have a significantly increased risk (OR, 2.03) of breast cancer as compared with noncarriers after adjustment for the classical epidemiological risk factors. Although a statistical significance has not been attained, the variant allele carriers are associated with an increased risk of breast cancer both in premenopausal women (OR, 2.22) and postmenopausal women (OR, 1.90), suggesting that this genetic polymorphism confers a risk irrespective of the menopausal status. BRCA2 has been revealed to form a complex with Rad51 and is involved in the repair of double-strand DNA breaks as well as in mitotic and meiotic recombination (12) . It is currently unknown whether the variant allele (V784) increases the breast cancer risk through affecting the function of BRCA2 or whether it is in linkage disequilibrium with other functional polymorphisms. The variant allele frequency of the M/V784 polymorphism has not yet been reported. No linkage was observed between M/V784 and N/H372 polymorphisms in the present study.

Consistent with the report that hereditary breast cancers arising in BRCA2 germ-line mutation carriers show no distinctive pathobiological phenotypes as compared with sporadic breast cancers (13 , 14) , breast cancers arising in the variant allele (V784) carriers were found to show phenotypes similar to those of the variant allele noncarriers. Although the impact of BRCA2 germ-line mutation on prognosis is still controversial, a few reports have suggested its association with poor prognosis (15 , 16) . Interestingly, we could demonstrate a significant association of the variant allele (V784) with poor prognosis; this association was confirmed by multivariate analysis, indicating that BRCA2 M/V784 polymorphism can serve as a significant prognostic factor being independent of the other classical prognostic factors such as lymph node status and ER status. Our present observation seems to suggest that the BRCA2 M/V784 polymorphism might be useful not only in assessing the risk of developing breast cancer but also in predicting the patient prognosis. Ideally, a new prognostic factor is to be tested in those patients who are without adjuvant therapy. However, almost all breast cancer patients are recently treated with adjuvant therapy. Thus, nowadays it is practically infeasible to evaluate a new prognostic factor among patients without adjuvant therapy. Thus, it is currently unknown whether the BRCA2 (M/V784) polymorphism is a real prognostic factor or a predictive factor in response to adjuvant therapy.

Until now, several BRCA2 polymorphisms (a-26g, N/H298, N/H372, Thr (T)/M1915, R/Cys (C) 2034, and Lys (K)/X3326) have been studied in their association with breast cancer risk, and only one polymorphism (N/H372) has been shown to be significantly associated with breast cancer risk, i.e., homozygotes of H372 allele show a 1.3- or 1.4-fold increase in breast cancer risk (7 , 8) . Our present study, however, has failed to show such a significant association with regard to the N/H372 polymorphism. This inconsistency might be explained by the difference in sample size between the British cohort and ours (the British cohort is at least 10 times larger than our cohort) and by racial difference. The recently published British population-based study (17) has reported that this N/H372 polymorphism is not significantly associated with patient prognosis, which is consistent with our present observation.

In conclusion, we have shown that women with a variant allele (V784) of BRCA2 are at a significantly increased risk of developing breast cancer, and that breast cancer patients with this allele are at a significantly increased risk of developing recurrences. Although many reports have been available on the relationship between various genetic polymorphisms and breast cancer risk, the impact of these genetic polymorphisms on prognosis has rarely been studied in breast cancer patients, but it is possible, as suggested in the present study, that a certain genetic polymorphism is associated both with breast cancer risk and with patient prognosis.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by grants from Ministry of Education, Culture, Sports, Science and Technology, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Surgical Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3772; Fax: 81-6-6879-3779; E-mail: noguchi{at}onsurg.med.osaka-u.ac.jp Back

3 The abbreviations used are: DFS, disease-free survival; SSCP, single-strand conformational polymorphism; ER, estrogen receptor; OR, odds ratio; CI, confidential interval. Back

Received 8/19/02; revised 12/ 3/02; accepted 12/ 6/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fisher B., Costantino J. P., Wickerham D. L., Redmond C. K., Kavanah M., Cronin W. M., Vogel V., Robidoux A., Dimitrov N., Atkins J., Daly M., Wieand S., Tan-Chiu E., Ford L., Wolmark N. Tamoxifen for the prevention of breast cancer: report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl. Cancer Inst. (Bethesda), 90: 1371-1388, 1998.[Abstract/Free Full Text]
  2. Gail M. H., Brinton L. A., Byar D. P., Corle D. K., Green S. B., Schairer C., Mulvihill J. J. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J. Natl. Cancer Inst. (Bethesda), 81: 1879-1886, 1989.[Abstract/Free Full Text]
  3. Dunning A. M., Healey C. S., Pharoah P. D. P., Teare D. M., Ponder B. A. J., Easton D. F. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol. Biomark. Prev., 8: 843-854, 1999.[Abstract/Free Full Text]
  4. Easton D. F., Bishop D. T., Ford D., Crockford G. P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet., 52: 678-701, 1993.[Medline]
  5. Dunning A. M., Chiano M., Smith N. R., Dearden J., Gore M., Oakes S., Wilson C., Stratton M., Peto J., Easton D., Clayton D., Ponder B. A. Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum. Mol. Genet., 6: 285-289, 1997.[Abstract/Free Full Text]
  6. Durocher F., Shattuck-Eidens D., McClure M., Labrie F., Skolnick M. H., Goldgar D. E., Simard J. Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum. Mol. Genet., 6: 835-842, 1996.
  7. Healey C. S., Dunning A. M., Dawn Teare M., Chase D., Parker L., Burn J., Chang-Claude J., Mannermaa A., Kataja V., Huntsman D. G., Pharoah P. D., Luben R. N., Easton D. F., Ponder B. A. A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nat. Genet., 26: 362-364, 2000.[CrossRef][Medline]
  8. Spurdle A. B., Hopper J. L., Chen X., Dite G. S., Cui J., McCredie M. R. E., Giles G. G., Ellis-Steinborner S., Venter D. J., Newman B., Southey M. C., Chenevix-Trench G. The BRCA2 372 HH genotype is associated with risk of breast cancer in Australian women under age 60 years. Cancer Epidemiol. Biomark. Prev., 11: 413-416, 2002.[Abstract/Free Full Text]
  9. Ikeda N., Miyoshi Y., Yoneda K., Shiba E., Sekihara Y., Kinoshita M., Noguchi S. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int. J. Cancer, 91: 83-88, 2001.[CrossRef][Medline]
  10. Elston C. W. Grading of invasive carcinoma of the breast Page D. L. Anderson T. J. eds. . Diagnostic Histopathology of the Breast, 300-311, Churchill Livingstone Edinburgh 1987.
  11. Goldhirsch A., Wood W. C., Senn H. J., Glick J. H., Gelber R. D. Fifth International Conference on Adjuvant Therapy of Breast Cancer, St. Gallen, March 1995. International Consensus Panel on the Treatment of Primary Breast Cancer. Eur. J. Cancer, 31: 1754-1759, 1995.[CrossRef]
  12. Chen J., Silver D. P., Walpita D., Cantor S. B., Gazdar A. F., Tomlinson G., Couch F. J., Weber B. L., Ashley T., Livingston D. M., Scully R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol. Cell, 2: 317-328, 1998.[CrossRef][Medline]
  13. Noguchi S., Kasugai T., Miki Y., Fukutomi T., Emi M., Nomizu T. Clinicopathologic analysis of BRCA1- or BRCA2-associated hereditary breast carcinoma in Japanese women. Cancer (Phila.), 85: 2200-2205, 1999.[CrossRef][Medline]
  14. Phillips K. A., Andrulis I. L., Goodwin P. J. Breast carcinomas arising in carriers of mutations in BRCA1 or BRCA2are they prognostically different?. J. Clin. Oncol., 17: 3653-3663, 1999.[Abstract/Free Full Text]
  15. Eerola H., Vahteristo P., Sarantaus L., Kyyrönen P., Pyrhönen S., Blomqvist C., Pukkala E., Nevanlinna H., Sankila R. Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland. Int. J. Cancer, 93: 368-372, 2001.[CrossRef][Medline]
  16. Loman N., Johannsson O., Bendahl P. O., Dahl N., Einbeigi Z., Gerdes A. M., Borg A., Olsson H. Prognosis and clinical presentation of BRCA2 associated breast cancer. Eur. J. Cancer, 36: 1365-1373, 2000.
  17. Goode E. L., Dunning A. M., Kuschel B., Healey C. S., Day N. E., Ponder B. A. J., Easton D. F., Pharoah P. P. D. Effect of germ-line genetic variation on breast cancer survival in a population-based study. Cancer Res., 62: 3052-3057, 2002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
D. J. Hughes, S. M. Ginolhac, I. Coupier, M. Corbex, B. Bressac-de-Paillerets, A. Chompret, Y.-J. Bignon, N. Uhrhammer, C. Lasset, S. Giraud, et al.
Common BRCA2 Variants and Modification of Breast and Ovarian Cancer Risk in BRCA1 Mutation Carriers
Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 265 - 267.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. L. Freedman, K. L. Penney, D. O. Stram, L. Le Marchand, J. N. Hirschhorn, L. N. Kolonel, D. Altshuler, B. E. Henderson, and C. A. Haiman
Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort
Hum. Mol. Genet., October 1, 2004; 13(20): 2431 - 2441.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
M D Teare, A Cox, J Shorto, C Anderson, D T Bishop, and C Cannings
Heterozygote excess is repeatedly observed in females at the BRCA2 locus N372H
J. Med. Genet., July 1, 2004; 41(7): 523 - 528.
[Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Zhu, M. R. Spitz, C. I. Amos, J. Lin, M. B. Schabath, and X. Wu
An Evolutionary Perspective on Single-Nucleotide Polymorphism Screening in Molecular Cancer Epidemiology
Cancer Res., March 15, 2004; 64(6): 2251 - 2257.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ishitobi, M.
Right arrow Articles by Noguchi, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ishitobi, M.
Right arrow Articles by Noguchi, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation