BRCA1/2 associated hereditary breast cancer

BRCA1/2 associated hereditary breast cancer first-author †E-mail:lsteng@zju.edu.cn †E-mail:lsteng@zju.edu.cn lsteng@zju.edu.cn Cancer Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Cancer Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes, focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial; further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers. BRCA1 BRCA2 Hereditary breast cancer INTRODUCTION 1 Although the advancement of diagnostic techniques and treatment in the last decade has greatly contributed to the survival of cancer patients, breast cancer is still one of the leading causes of death in women today. It is estimated that there are approximately 180 510 new occurrences of breast cancer and 40 910 breast cancer deaths (40 460 women, 450 men) in the year of 2007 in the US (American Cancer Society, 2007 2007 ). Among breast cancer patients, up to 5%~10% are considered directly relating to the inheritance of mutation in BRCA1 or BRCA2 (Claus et al., 1996 1996 ), which accounts for most of the hereditary breast cancers. Moreover, women carrying these mutations have a lifetime breast cancer risk of 60%~80% (Easton et al., 1993 1993 ; Struewing et al., 1996 1996 ); therefore, detection of mutation in these two genes can serve as a molecular predictor for women with a family history of breast cancer. As a consequence of current trends in multidisciplinary therapy for breast cancers, BRCA1 and BRCA2 , like other genes, have not only served as molecular markers for hereditary breast cancer risk screening, but also become important indicators for breast cancer prevention, treatment and prognosis. In this review, we provide an overview of these two well-known breast cancer susceptibility genes, focusing on their relationship with hereditary breast cancers. FUNCTIONS AND MUTATIONS 1 BRCA1 was first located to chromosome 17 via a genetic linkage analysis in 23 early-onset breast cancer families (Hall et al., 1990 1990 ), and was cloned and isolated in 1994 (Miki et al., 1994 1994 ). Further research had localized it to 17q21 with a length of 100 kb. BRCA1 has 24 exons, including 2 non-translating exons, encoding a protein of 1 863 amino acids, which is characterized by a zinc-binding RING-finger domain at the amino terminus and BRCA1 carboxyl-terminal (BRCT) domain at the carboxyl terminus. BRCA1 is classified as a tumor suppressor gene and plays an important role in surveillance of cell cycle and repair of DNA damage. Evidence shows that BRCA1 is phosphorylated by the checkpoint kinase ataxia telangiectasia mutated (ATM) protein after ionizing radiation (Cortez et al., 1999 1999 ). Mediator of DNA damage checkpoint protein 1 (MDC1) can regulate BRCA1 to the sites of DNA lesions and phosphorylate it through ATM dependent pathways (Lou et al., 2003 2003 ). After activation, BRCA1 can bind to p53, RAD50-MRE11-NBS1 (R-M-N) complex and RAD51, conducting homologous recombination or non-homologous end-joining (NHEJ) which is of great importance in DNA damage repair. The zinc-binding RING-finger domain of BRCA1 can interact with BRCA1 associated RING domain 1 (BARD1) forming a heterodimeric complex that has ubiquitin ligase activity (Hashizume et al., 2001 2001 ), and the complex itself may be involved in DNA damage repair. In 1995, a second gene termed BRCA2 was found related to hereditary breast cancer (Wooster et al., 1995 1995 ). It covers about 70 kb of genomic sequence in 13q12, encoding a protein of 3 418 amino acids. The coding region of BRCA2 is composed of 27 exons with a non-translating exon. However, the gene sequence of BRCA2 bears no obvious homology to any known gene including BRCA1 , and the protein contains no defined functional domains (Tavtigian et al., 1996 1996 ; Wooster et al., 1995 1995 ). BRCA2 can bind with BRCA1, participating in DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair (Chen et al., 1999 1999 ). For their key role in maintaining genomic integrity and supervising cell cycle, mutations in BRCA1 and BRCA2 are found strongly related to hereditary breast cancers. However, the types of mutation differ in distribution by ethnicity and geographic location. The “hot spot” sites of mutation for Ashkenazi Jewish are present at 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 (Abeliovich et al., 1997 1997 ), whereas 3171ins5 is the characterized mutation from high-risk families examined in Sweden (Einbeigi et al., 2001 2001 ). The prevalence of mutations in BRCA1 and BRCA2 also varies in diverse populations. For example, the BRCA1 mutation frequency in Finnish breast cancer patients is 0.4% (Syrjakoski et al., 2000 2000 ), whereas by contrast the number for its neighbor country, Sweden, is 7% (Zelada-Hedman et al., 1997 1997 ). Among all the genetic alterations in BRCA1 and BRCA2 , 85% are frameshift or nonsense mutations, yielding a truncated protein product (Struewing et al., 1995 1995 ). The cells, therefore, have a decreased ability to repair damaged DNA; the genomic instability is observed in animal models due to this defect (Yu et al., 2000 2000 ). Tumor tissues from carriers of mutant BRCA1 or BRCA2 gene are presented with chromosomal abnormalities including losses of 5q, 4q, 4p, 2q, 12q, 13q and 6q significantly more commonly than the normal control group (Tirkkonen et al., 1997 1997 ). PATHOLOGY 1 Hereditary breast cancers arising in carriers of BRCA1 and/or BRCA2 genes mutations differ from sporadic breast cancers of age-matched controls and from non- BRCA1/2 hereditary breast carcinomas in their morphological, immunophenotypic and molecular characteristics. BRCA1 associated breast carcinomas have the “basal-like” phenotype (Perou et al., 2000 2000 ), a subtype of high grade (usually Grade 3), high mitotic count, estrogen receptor (ER) and Her2 negative carcinomas (Breast Cancer Linkage Consortium, 1997 1997 ; Lakhani et al., 1998 1998 ), characterized by the expression of basal or myoepithelial markers such as basal keratins (Foulkes et al., 2003 2003 ), P-cadherin, epidermal growth factor receptor, etc. (Honrado et al., 2005 2005 ). BRCA1 associated breast carcinomas usually have the over-expressions of the cell-cycle proteins such as cyclins A, B1 and E, and S-phase kinase-associated protein 2 (SKP2) (Honrado et al., 2005 2005 ). BRCA2 associated breast carcinomas are rarely that “basal-like” phenotype, but a subtype that has higher grade (usually Grade 2/3) than sporadic age-matched controls (Breast Cancer Linkage Consortium, 1997 1997 ), and tend to be ER and progesterone receptor (PR) positive (Lakhani et al., 2002 2002 ; Robson et al., 2004 2004 ). BRCA2 associated breast carcinomas usually have the over-expressions of cyclin D1 and p27 (Honrado et al., 2005 2005 ). Recent studies have shown that non- BRCA1/2 associated breast cancers tend to have lower grades and mitotic counts than BRCA1/2 associated hereditary breast cancers (Honrado et al., 2005 2005 ). PREVENTION 1 Penetrance refers to the probability of developing disease in a carrier of a deleterious mutation and is usually detected at a given age. It appears that the risk of cancer among women who carry a BRCA1 or BRCA2 mutation could be modified by some specific genes or by an environmental factor and lifestyles. In the case of hereditary breast cancers, the candidate modifier genes that have been studied are related to the metabolism of sex hormones and to DNA repair. Four genes, Androgen Receptor ( AR ), Nuclear Receptor Coactivator 3 ( NCOA3 ), RAD51 and H - ras , have been suggested as potential modifiers of risk in BRCA1 or BRCA2 mutation carriers, but the evidence for these is too weak to guide clinical practice (Narod, 2002 2002 ). Hormonal factors (oophorectomy, pregnancy, breastfeeding, oral contraceptives, tubal ligation, tamoxifen, hormone replacement therapy, etc.) have also been tried to modify the risk of breast cancer. Some studies indicate that oophorectomy reduces risk in BRCA1 mutation carriers and probably in BRCA2 mutation carriers, whereas tamoxifen reduces the risk in BRCA2 mutation carriers (King et al., 2001 2001 ) and probably in BRCA1 mutation carriers (Narod et al., 2000 2000 ), although ER status is usually negative in those BRCA1 mutation carriers. Women with a BRCA1 or BRCA2 mutation who have a high risk of breast cancer could choose to undergo prophylactic bilateral total mastectomy, which reduces the incidence of breast cancer at three years of follow-up (Meijers-Heijboer et al., 2001 2001 ). In another study, data indicate that the majority of women reported satisfaction with bilateral prophylactic mastectomy; in the meantime, they experienced psychosocial outcomes similar to those with similarly elevated breast cancer risk who did not undergo prophylactic mastectomy. Bilateral prophylactic mastectomy appears to have neither positive nor negative impact on long-term psychosocial outcomes (Geiger et al., 2007 2007 ). According to recent research results, women who are BRCA1/2 mutation carriers and have a history of breast cancer or ductal carcinoma in situ (DCIS), or a family history of ovarian cancer, are more likely to have undergone surgical procedures for risk reduction (Uyei et al., 2006 2006 ). At present, it is much more difficult to develop risk-assessment tools to take into consideration all established risk factors including mutation type and position, reproductive history, exogenous hormone level, and the specific relevant modifying genes. PROGNOSIS 1 Prognosis of patients carrying mutant BRCA1 or BRCA2 compared with general breast cancer populations still remains controversial. Several studies have proved that patients with BRCA1 mutation have poor outcome. A research program at collaborating centers in Norway and the UK found that the five-year survival in BRCA1 -mutated patients is 73% compared to 92% in mutation-negative patients ( P < 0.001) (Moller et al., 2007 2007 ). One study from 496 Jewish women with breast cancer showed a similar result that the rate of breast cancer specific survival after a median follow-up period of 116 months is worse for BRCA1 mutants than for non-carriers (62% vs 86%, P < 0.0001) (Robson et al., 2004 2004 ). On the contrary, some studies reported no significant differences of survival data existing between women with BRCA1 mutations and those without. One study on Israeli women concluded that breast cancer specific rates of death are similar between carriers of a BRCA1/2 founder mutation and non-carriers, with the hazard ratio among BRCA1 carriers to be 0.76 and 95% confidence interval (CI) 0.45~1.30, P =0.31; and the hazard ratio among BRCA2 carriers to be 1.3 and 95% CI 0.80~2.15, P =0.28 (Rennert et al., 2007 2007 ). Another two studies conducted in New York and Rotterdam presented the same negative results that breast cancer specific survival is similar between the mutation carriers and non-carriers in breast cancer patients and patients at high risk for breast cancer, respectively (El-Tamer et al., 2004 2004 ; Brekelmans et al., 2006 2006 ). Because of the controversial results, whether there is a real difference in survival data remains unclear. More attention is needed to examine the variable factors, such as ER status, lymph node involvement, and cancer staging. SUMMARY 1 About one decade has passed since the discovery of the BRCA1/2 genes, and we have come to realize the constructions and major functions of BRCA1/2 proteins and also the close relationship between BRCA1/2 mutations and hereditary breast cancers. BRCA1/2 genes are tumor suppressor genes, the mutations of which could result in hereditary breast cancers. Several measures have been tried to reduce the risk of hereditary breast cancers. The initial results after prophylactic oophorectomy/bilateral prophylactic mastectomy and oral administration of tamoxifen show their effects on risk reduction. BRCA1/2 associated breast cancers have their own pathologic characteristics. However, prognosis of patients carrying mutant BRCA1/2 compared with general breast cancer populations still remains controversial. The further elucidation on the relationship between BRCA1/2 mutations and hereditary breast cancer remains a task in the future. References D Abeliovich , L Kaduri , I Lerer , N Weinberg , G Amir , M Sagi , J Zlotogora , N Heching , T Peretz . The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-on-set breast cancer patients among Ashkenazi women . Am J Hum Genet , 1997 . 60 ( 3 ): 505 - 514 . . The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-on-set breast cancer patients among Ashkenazi women American Cancer Society Cancer Facts and Figures , 2007 . 3 - 9 . (Available from: Http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2007.asp Http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2007.asp ) . Cancer Facts and Figures Breast Cancer Linkage Consortium Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases . Lancet , 1997 . 349 ( 9064 ): 1505 - 1510 . . Pathology of familial breast cancer: Differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases CTM Brekelmans , C Seynaeve , M Menke-Pluymers , HT Brüggenwirth , MMA Tilanus-Linthorst , CCM Bartels , M Kriege , AN van Geel , CMG Crepin , JC Blom , 等 . Survival and prognostic factors in BRCA1 -associated breast cancer . Ann Oncol , 2006 . 17 ( 3 ): 391 - 400 . DOI: 10.1093/annonc/mdj095 http://doi.org/10.1093/annonc/mdj095 . Survival and prognostic factors in BRCA1-associated breast cancer JJ Chen , D Silver , S Cantor , DM Livingston , R Scully . BRCA1 , BRCA2 , and Rad51 operate in a common DNA damage response pathway . Cancer Res , 1999 . 59 ( 7 Suppl. ): 1752 - 1756 . . BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway EB Claus , JM Schildkraut , WD Thompson , NJ Risch . The genetic attributable risk of breast and ovarian cancer . Cancer , 1996 . 77 ( 11 ): 2318 - 2324 . DOI: 10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z http://doi.org/10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z . The genetic attributable risk of breast and ovarian cancer D Cortez , Y Wang , J Qin , SJ Elledge . Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks . Science , 1999 . 286 ( 5442 ): 1162 - 1166 . DOI: 10.1126/science.286.5442.1162 http://doi.org/10.1126/science.286.5442.1162 . Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks DF Easton , DT Bishop , D Ford , GP Crockford . Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families . Am J Hum Genet , 1993 . 52 ( 4 ): 678 - 701 . The Breast Cancer Linkage Consortium . Genetic linkage analysis in familial breast and ovarian cancer: Results from 214 families Z Einbeigi , A Bergman , LG Kindblom , T Martinsson , JM Meis-Kindblom , M Nordling , M Suurküla , J Wahlström , A Wallgren , P Karlsson . A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer . Eur J Cancer , 2001 . 37 ( 15 ): 1904 - 1909 . DOI: 10.1016/S0959-8049(01)00223-4 http://doi.org/10.1016/S0959-8049(01)00223-4 . A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer M El-Tamer , D Russo , A Troxel , LP Bernardino , R Mazziotta , A Estabrook , B Ditkoff , F Schnabel , M Mansukhani . Survival and recurrence after breast cancer in BRCA1/2 mutation carriers . Ann Surg Oncol , 2004 . 11 ( 2 ): 157 - 164 . DOI: 10.1245/ASO.2004.05.018 http://doi.org/10.1245/ASO.2004.05.018 . Survival and recurrence after breast cancer in BRCA1/2 mutation carriers WD Foulkes , IM Stefansson , PO Chappuis , LR Begin , JR Goffin , N Wong , M Trudel , LA Akslen . Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer . J Natl Cancer Inst , 2003 . 95 ( 19 ): 1482 - 1485 . DOI: 10.1093/jnci/djg050 http://doi.org/10.1093/jnci/djg050 . Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer AM Geiger , L Nekhlyudov , LJ Herrinton , SJ Rolnick , SM Greene , CN West , EL Harris , JG Elmore , A Altschuler , IL Liu , 等 . Quality of life after bilateral prophylactic mastectomy . Ann Surg Oncol , 2007 . 14 ( 2 ): 686 - 694 . DOI: 10.1245/s10434-006-9206-6 http://doi.org/10.1245/s10434-006-9206-6 . Quality of life after bilateral prophylactic mastectomy JM Hall , MK Lee , B Newman , JE Morrow , LA Anderson , B Huey , MC King . Linkage of early-onset familial breast cancer to chromosome 17q21 . Science , 1990 . 250 ( 4988 ): 1684 - 1689 . DOI: 10.1126/science.2270482 http://doi.org/10.1126/science.2270482 . Linkage of early-onset familial breast cancer to chromosome 17q21 R Hashizume , I Fukuda , H Maeda , H Nishikawa , D Oyake , Y Yabuki , H Ogata , T Ohta . The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation . J Biol Chem , 2001 . 276 ( 18 ): 14537 - 14540 . DOI: 10.1074/jbc.C000881200 http://doi.org/10.1074/jbc.C000881200 . The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation E Honrado , J Benítez , J Palacios . The molecular pathology of hereditary breast cancer: Genetic testing and therapeutic implications . Mod Pathol , 2005 . 18 ( 10 ): 1305 - 1320 . DOI: 10.1038/modpathol.3800453 http://doi.org/10.1038/modpathol.3800453 . The molecular pathology of hereditary breast cancer: Genetic testing and therapeutic implications MC King , S Wieand , K Hale , M Lee , T Walsh , K Owens , J Tait , L Ford , BK Dunn , J Costantino , 等 . Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2 : National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial . JAMA , 2001 . 286 ( 18 ): 2251 - 2256 . DOI: 10.1001/jama.286.18.2251 http://doi.org/10.1001/jama.286.18.2251 . Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial SR Lakhani , J Jacquemier , JP Sloane , BA Gusterson , TJ Anderson , MJ Vijver , LM Farid , D Venter , A Antoniou , A Storfer-Isser , 等 . Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations . J Natl Cancer Inst , 1998 . 90 ( 15 ): 1138 - 1145 . DOI: 10.1093/jnci/90.15.1138 http://doi.org/10.1093/jnci/90.15.1138 . Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations SR Lakhani , MJ van de Vijver , J Jacquemier , TJ Anderson , PP Osin , L McGuffog , DF Easton . The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2 . J Clin Oncol , 2002 . 20 ( 9 ): 2310 - 2318 . DOI: 10.1200/JCO.2002.09.023 http://doi.org/10.1200/JCO.2002.09.023 . The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2 Z Lou , CC Chini , K Minter-Dykhouse , J Chen . Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control . J Biol Chem , 2003 . 278 ( 16 ): 13599 - 13602 . DOI: 10.1074/jbc.C300060200 http://doi.org/10.1074/jbc.C300060200 . Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control H Meijers-Heijboer , B van Geel , WLJ van Putten , SC Henzen-Logmans , C Seynaeve , MB Menke-Pluymers , CC Bartels , LC Verhoog , AMW van den Ouweland , MF Niermeijer , 等 . Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation . N Engl J Med , 2001 . 345 ( 3 ): 159 - 164 . DOI: 10.1056/NEJM200107193450301 http://doi.org/10.1056/NEJM200107193450301 . Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation Y Miki , J Swensen , D Shattuck-Eidens , PA Futreal , K Harshman . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 . Science , 1994 . 266 ( 5182 ): 66 - 71 . DOI: 10.1126/science.7545954 http://doi.org/10.1126/science.7545954 . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 P Moller , DG Evans , MM Reis , H Gregory , E Anderson , L Maehle , F Lalloo , A Howell , J Apold , N Clark , 等 . Surveillance for familial breast cancer: Differences in outcome according to BRCA mutation status . Int J Cancer , 2007 . 121 ( 5 ): 1017 - 1020 . DOI: 10.1002/ijc.22789 http://doi.org/10.1002/ijc.22789 . Surveillance for familial breast cancer: Differences in outcome according to BRCA mutation status SA Narod . Modifiers of risk of hereditary breast and ovarian cancer . Nat Rev Cancer , 2002 . 2 ( 2 ): 113 - 123 . DOI: 10.1038/nrc726 http://doi.org/10.1038/nrc726 . Modifiers of risk of hereditary breast and ovarian cancer SA Narod , JS Brunet , P Ghadirian , M Robson , K Heimdal , SL Neuhausen , D Stoppa-Lyonnet , C Lerman , B Pasini , P Rios , 等 . Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study . Lancet , 2000 . 356 ( 9245 ): 1876 - 1881 . DOI: 10.1016/S0140-6736(00)03258-X http://doi.org/10.1016/S0140-6736(00)03258-X . Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study CM Perou , T Sorlie , MB Eisen , M Rijn , SS Jeffrey , CA Rees , JR Pollack , DT Ross , H Johnsen , LA Akslen , 等 . Molecular portraits of human breast tumours . Nature , 2000 . 406 ( 6797 ): 747 - 752 . DOI: 10.1038/35021093 http://doi.org/10.1038/35021093 . Molecular portraits of human breast tumours G Rennert , S Bisland-Naggan , O Barnett-Griness , N Bar-Joseph , S Zhang , HS Rennert , SA Narod . Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations . N Engl J Med , 2007 . 357 115 - 123 . DOI: 10.1056/NEJMoa070608 http://doi.org/10.1056/NEJMoa070608 . Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations ME Robson , PO Chappuis , J Satagopan , N Wong , J Boyd , JR Goffin , C Hudis , D Roberge , L Norton , LR Bégin , 等 . A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment . Breast Cancer Res , 2004 . 6 ( 1 ): R8 - R17 . DOI: 10.1186/bcr658 http://doi.org/10.1186/bcr658 . A combined analysis of outcome following breast cancer: Differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment JP Struewing , D Abeliovich , T Peretz , N Avishai , MM Kaback , FS Collins , LC Brody . The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals . Nat Genet , 1995 . 11 ( 2 ): 198 - 200 . DOI: 10.1038/ng1095-198 http://doi.org/10.1038/ng1095-198 . The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals JP Struewing , RE Tarone , LC Brody , FP Li , JD Boice . BRCA1 mutations in young women with breast cancer . Lancet , 1996 . 347 ( 9013 ): 1493 DOI: 10.1016/S0140-6736(96)91732-8 http://doi.org/10.1016/S0140-6736(96)91732-8 . BRCA1 mutations in young women with breast cancer K Syrjakoski , P Vahteristo , H Eerola , A Tamminen , K Kivinummi , L Sarantaus , K Holli , C Blomqvist , OP Kallioniemi , T Kainu , 等 . Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients . J Natl Cancer Inst , 2000 . 92 ( 18 ): 1529 - 1531 . DOI: 10.1093/jnci/92.18.1529 http://doi.org/10.1093/jnci/92.18.1529 . Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients SV Tavtigian , J Simard , J Rommens , F Couch , D Shattuck-Eidens , S Neuhausen , S Merajver , S Thorlacius , K Offit , D Stoppa-Lyonnet , 等 . The complete BRCA2 gene and mutations in chromosome 13q linked kindreds . Nat Genet , 1996 . 12 ( 3 ): 333 - 337 . DOI: 10.1038/ng0396-333 http://doi.org/10.1038/ng0396-333 . The complete BRCA2 gene and mutations in chromosome 13q linked kindreds M Tirkkonen , O Johannsson , BA Agnarsson , H Olsson , S Ingvarsson , R Karhu , M Tanner , J Isola , RB Barkardottir , A Borg , 等 . Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations . Cancer Res , 1997 . 57 ( 7 ): 1222 - 1227 . . Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations A Uyei , SK Peterson , J Erlichman , K Broglio , S Yekell , K Schmeler , K Lu , F Meric-Bernstam , C Amos , L Strong , 等 . Association between clinical characteristics and risk-reduction interventions in women who underwent BRCA1 and BRCA2 testing: A single-institution study . Cancer , 2006 . 107 ( 12 ): 2745 - 2751 . DOI: 10.1002/cncr.22352 http://doi.org/10.1002/cncr.22352 . Association between clinical characteristics and risk-reduction interventions in women who underwent BRCA1 and BRCA2 testing: A single-institution study R Wooster , G Bignell , J Lancaster , S Swift , S Seal , J Mangion , N Collins , S Gregory , C Gumbs , G Micklem . Identification of the breast cancer susceptibility gene BRCA2 . Nature , 1995 . 378 ( 6559 ): 789 - 792 . DOI: 10.1038/378789a0 http://doi.org/10.1038/378789a0 . Identification of the breast cancer susceptibility gene BRCA2 V Yu , M Koehler , C Steinlein , M Schmid , L A Hanakahi , AJ van Gool , SC West , AR Venkitaraman . Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation . Genes Dev , 2000 . 14 ( 11 ): 1400 - 1406 . . Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation M Zelada-Hedman , BW Arver , A Claro , J Chen , B Werelius , H Kok , K Sandelin , S Håkansson , TI Andersen , A Borg , 等 . A screening for BRCA1 mutations in breast and breast-ovarian cancer families from the Stockholm region . Cancer Res , 1997 . 57 ( 12 ): 2474 - 2477 . . A screening for BRCA1 mutations in breast and breast-ovarian cancer families from the Stockholm region 10.1631/jzus.B0710617 Project supported by the National Natural Science Foundation of China (No. 30772510) and the Joint Program of Ministry of Health and Zhejiang Provincal Government of China (No. WKJ2006-2-008) 2007-12-08 2007-12-13 2008-01-06 2022-01-05 Copyright © 2008, Journal of Zhejiang University Science 2008 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 02 09