(PDF) Scratch Video revisited

CGC International Journal of Contemporary Technology & Research ISSN: 2582-0486 (online), Vol.-2, Issue -1 DOI: 10.46860/cgcijctr/2019.12.30.48 Hereditary Breast Cancer: A Systematic Review *Preeti Chauhan1, Arockia M Babu2, Palki sahib kaur3, vikas Menon4 1,2,3,4ChandigarhCollege of Pharmacy, Landran, 140307, Mohali, Punjab, India *

Abstract: —Breast cancer is a heterogeneous group of tumours with variable prognosis. It is the second leading cause of cancer related death among women.Hereditary breast cancers (HBC) showed around ten percent of the total burden of breast cancer. Most of the breast cancer cases found due to a BRCA germ line mutation. According to estimation, 15–20% breast cancer patients to have one or more 1st or 2nd degree relatives affected with breast cancer. The factors included the genotypic and phenotypic heterogeneity. Many studies found association of HBC with different carcinoma syndromes. The most common association is with ovarian carcinoma so known as hereditary breast ovarian (BO) carcinoma syndrome involving BRCA1 and 2 mutations. Some other factors like reproductive risk factors including age at diagnosis of breast cancer, pregnancy history, and twin history were also studied and were found associated with breast cancer risk. In this review it is reported that knowledge of genetics of hereditary breast cancers may contribute to identification of patient’s increased risk of disease. These patients could be subjected to genetic counseling that can be definitely benefited from early diagnosis. Keywords: BRCA1, BRCA2, Hereditary breast cancer, reproductive risk factors, genetic counseling I. INTRODUCTION patient was the 2oproband called as the mother pedigree group. On the other hand where a sister was 2oproband called the sister Heredity is an established risk factor of breast pedigree group. Remained groups considered as second degree carcinoma. It is used to characterize the women who are at group [10-12]. higher risk. The effect of breast cancer risk factors in women with a family history is not very much defined [1]. Hereditary breast cancer accounts for approximately ten percent of total burden of breast cancer. Some studies introduced a well- structured model for breast cancer incidence that included age at menarche, children, history, age at menarche and menopause. According to this model, first child birth was associated with an increase in breast cancer risk, after that a subsequent decrease in risk [1]. Some studies showed the differentiation of breast tissue Figure 1: Pedigree structure of the hereditary breast at the 1stchild birth and lower susceptibility to carcinogens after carcinoma. Solidus; Diseased. Roman numerals; generations 1st birth [2, 3]. Reproductive history and other established risk (I-III). Proband; shading and arrow. Squares and circles; factors may influence the risk of breast cancer differently among males and females, respectively. Carriers; dot within the women having or not having a family history of breast cancer. In square or circle. mid 1990s, BRCA mutation testing became available. BRCA Some studies reported that 1stdegree relatives were permitted an accurate high risk candidate for this disease [4]. characterized by high breast cancer risks; whereas the sister and The hereditary breast cancer susceptible families were second degree pedigree groups are characterized by lower breast identified by hereditary breast and ovarian cancer (HBOC) carcinoma risk [13, 14].The genetic effect would be expected to syndrome that carried BRCA1and BRCA2 mutations. HBOC be minimum in the 2nddegreepedigree group. The mother syndrome accounted for 30% of all hereditary breast cancer pedigree group included such a hereditary form of breast cancer, (HBC). So, around 70% of the HBC burden lacks mutations in where three generations affected with breast cancer that means BRCA1 and 2 [5, 6]. In spite of so much research throughout the that daughters of patients have about 27-32% possibility of world to identify additional mutations involved in HBOC, breast cancer development. however the results have remained unclear [7-9]. The hereditary breast cancers are site-specific disease [13]. Walsh et al. 2006 reported the mutation spectra of BRCA1 and These can be identified by the familial occurrences of associated BRCA2 which included other high penetrance. Around 12% carcinoma, like familial occurrence of early breast carcinoma breast cancer patients with severe family histories of breast related with soft tissue sarcomas or the familial association of cancer found negative for BRCA1 and BRCA2 mutations [6]. breast carcinoma and colon carcinoma [15, 16]. In an earlier Only 5% breast cancer cases carried a large genomic deletion or study, other hereditary types around 10% of the pedigrees were duplication in BRCA1 or 2 genes, or in other genes (CHEK 2 identified. However, they were not confined to any pedigree OR TP53) [6]. group and their removal had no important hereditary effect on the risks [17, 18]. II. LEVELS OF THE PEDIGREE GROUP III. AGE AT DIAGNOSIS Almost all studies classified the patients into three pedigree groups (Figure 1).The genetic relationship among the original Among familial breast cancer patients, the younger age at patient known as1o proband and other relative affected with diagnosis of breast cancer was observed in breast cancer patients breast cancer were known as 2o pro band was basis for defining as compare to the others [13, 14, 19, 20]. Early age in the three pedigree groups. In those pedigrees where mother of the familial patients is consistent with the results of a 2step mutation CGCIJCTR2019 www.cgcijctr.com Page 48 © All Rights Reserved to CGCIJCTR CGC International Journal of Contemporary Technology & Research ISSN: 2582-0486 (online), Vol.-2, Issue -1 DOI: 10.46860/cgcijctr/2019.12.30.48 model proposed by the scientist Knudson. This model predicted age and age at first birth and breast cancer risk [29]. The studied the patients with hereditary basis for disease will have an earlier incidence data from New York State showed that a crossover in age at onset than the patients with a non hereditary basis. Some breast cancer incidence between married & un married women studies supported this model and indicated first degree relatives at the age of 42 years. They observed that married women were identified by high breast carcinoma risks; on the other hand showed higher incidence than unmarried women before this age sister and 2nddegree relative’s pedigree groups were identified and lower incidence after this. by lower carcinoma risks [14]. A similar crossover of incidence has been reported in black and IV. RISK FACTORS ASSOCIATED WITH REPRODUCTIVE white women which was constant with the distribution of age at HISTORY first birth by race [30, 31]. Over many decades, black women in the US had increased rates of pregnancy as well as early age at In some studies, it was reported that there is a constant increase first child birth as compare with white women of US [32]. in the risk of breast carcinoma in a mother or sister with family history of breast cancer that was related by 1stpregnancy [1]. V. GENETIC MODIFICATION IN HEREDITARY BREAST CANCER Many studies found that parous women were at higher risk of Modification of genetic in breast cancer risk is characterized by breast carcinoma than the nulliparous women [1, 17, 21]. the increased incidence of breast carcinoma in women with a Women having no family history of breast cancer, 1 st child birth family history. Linkage analysis studies of families have showed were associated with high risk of breast cancer. Early pregnancy the high penetration of genes being the probable reason of and high number of children were related with decreased breast inherited breast carcinoma risk in families [33]. cancer risk. However, the bad effect of early menarche was Alterations in genes are quite rare, and account for around ten decreased in women having family history of breast cancer. In percent of breast carcinoma patients. It is possible that important postmenopausal women with family history of breast cancer, the background genetic factors may contribute to the etiology of bad effect of pregnancy persisted up to 70 years of age [22]. breast cancers [34]. Autosomal dominant inherited disposition to IV.1 Twins history breast cancer is identified by early age at onset of breast carcinoma i.e. transfer through both mother and father. Three Floderus et al. (1990) compared family history of breast cancer principal syndromes found associated with breast cancer risk i. by the twin babies with carcinoma [23]. They observed a 50% of e.: family history of breast cancer affected twins. The authors hypothesized that it was a conservative estimate, as twin babies (i) Due to BRCA1 or BRCA2 mutations could be in closer contact than siblings in general. Results from (ii) Li Fraumeni syndrome due to mutations in the p53 and the Iowa women's health study showed a lower relative risk for a family history of breast cancer in a first-degree relative. hCHK2 gene. Sometimes it is associated with the old age of that particular population [24]. (iii) Cowden syndrome due to PTEN mutations [35-37]. Mutations in these genes give different phenotypes of particular IV.2 Age at menarche carcinoma. Other syndromes, that included breast carcinoma, The effect of later age at menarche was taper off in women with may be ataxia telangiectasia and Peutz Jeghers syndrome. a family history of breast cancer [25]. The finding was Ataxia telangiectasia is primarily an autosomal recessive consistent with several other studies of risk factors among disorder. It is hypothesized that around 1one percent of the women with or without a family history of breast cancer [26, general population may be heterozygous carriers of ATM gene 27]. Data of the Iowa Women's Study indicated reproductive [38]. Over two hundred mutations have been identified in these factors were related differently with breast carcinoma risk genes till date. Maximum of those are truncated mutations [39]. related to family history. Many epidemiological studies have suggested a significant increased breast cancer risk among heterozygous carriers. The Later age at menarche showed a protective effect that is limited estimated relative risk studied ranged from 3.9 to 6.4 [40]. to women without a family history of breast cancer. Number of Peutz-Jeghers syndrome is an autosomal dominant live child births was not found related to breast cancer risk disorder(early onset) [41]. Germline mutations in S.T.K.1.1 among women without a family history. Analysis was based on found responsible for fifty percent of Peutz Jeghers syndrome classification according to age at first child birth or parity [24]. [42]. Patients having this syndrome hadaincreased breast IV.3 Pregnancy history cancerrisk [43]. Some studies reported that pregnancy after exposure to VI. BRCA1 &2 GENES carcinogens increases the rate of tumor growth as compared to BRCA1 gene is present on chromosome no. 17q21.It contains pregnancy before exposure [28]. Some studies found this term twenty four exons encoding a protein of 220 kDa. It is made up was statically significant only for 1stfull term pregnancy and not of 1863 amino acids (Figure 2) [33, 44]. The second breast for subsequent pregnancies. This hypothesis suggested that cancer causing gene i.e., BRCA2, is present on long arm of breast is expected to be protected against effects of cell chromosome no. 13. BRCA2 is a large gene, composed of proliferation during second & subsequent pregnancies [17]. twenty seven exons encoding a protein of 380 kDa [45]. Both Increase in breast cancer risk was found related with 1stfull term these genes are nonhomologous.BRCA1 &2 have a large exon pregnancy which was followed by a decrease rate of risk in the no.11 and translational start site in exon no. 2. Their proteins are rate of cell turnover. It also account for the interaction between normally located in the nucleus and containing phosphorylated CGCIJCTR2019 www.cgcijctr.com Page 49 © All Rights Reserved to CGCIJCTR CGC International Journal of Contemporary Technology & Research ISSN: 2582-0486 (online), Vol.-2, Issue -1 DOI: 10.46860/cgcijctr/2019.12.30.48 residues [44, 45]. BRCA1 gene contains two protein motifs and In both of these genes, alterations are distributed uniformly ring finger domain along with the BRCT domain near C along with the entire exonic as well as intronic sequences terminus. These domains may facilitate both PPI and PD flanking the exons. The alterations which are associated with interactions. The BRCT domain is a phylogenetic conserved high breast cancer risk results in complete protein miss or non sequence present in the proteins which are involved in DNA functional proteins. This supports the hypothesis that BRCA1 & repair as well as regulation of cell cycle [46]. 2 is tumor suppressor genes. It is suggested that BRCA1 & 2 mutations showed different expression w.r.t. breast, ovarian and other related cancers. A study on one hundred and six families was screened for BRCA1 & 2 point mutations and small deletions. Analysis of mutation was performed by the automatic direct sequencing technique. The total of different forty six families was found carriers for BRCA1&2 mutations. No mutations were found in 57% of families. Different other variants of uncertain molecular significance were also found. VIII. FREQUENCY DISTRIBUTION OF PATHOLOGICAL ALLELIC VARIANTS I.E. FOUNDER MUTATIONS The maximum number of BRCA alterations has been reported in Figure 2: Breast cancer causing genes BRCA2 & BRCA 2 many families. A small number of such mutations have been location on human chromosomes found in many families in the same ethnic group this is known as founder effects. Approximately one out of eight hundred BRCA2 has no protein motifs and no direct relationship with women in general population may carry alterations in BRCA1. other breast cancer causing gene BRCA1. Although BRCA1 and The percent frequency of BRCA1 mutation carriers has been BRCA2 share many functional similarities which suggest that reported in selected groups of families [55, 56]. how mutations in both of these genes have a specific hereditary disposition to breast cancer. However, accurate molecular The examples of founder mutations had been described in some function of both of these genes and their mutations inducing studies [58]. In this study the carrier percent frequencies for breast carcinoma remain unclear till now. However, it is also these mutations was determined in some studies [57]. Overall, observed that BRCA proteins are involved in many cellular the percentage frequency of such mutations is one in fifty functions, like integrity of genome, cell growth as well as cell Ashkenazi Jews. Around twenty five percent of early-onset differentiation [47, 48]. breast carcinoma and has been found in 90% of families [58].The founder mutations were found in Netherlands Evidences suggested that BRCA1 &2 is directly involved in the (BRCA1), Iceland (BRCA2) and Sweden (BRCA1) [59, 60]. DNA repair process, gene expression regulation & embryogenesis [47, 49, 50]. The end products of both of these Founder mutations have also been found in some areas of some genes i.e. proteins, get interacted with different other proteins restricted areas of Italy. A founder effect was identified in a which are associated with homologous chromosome country (Italy) for both BRCA1 & 2 [61, 62]. A new founder recombination and double stranded break repair mechanisms mutation was described in Tuscany. In this study, 10 haplotype [50]. These results are important for finding mechanisms of analysis of eleven families was detected (1499 ins) in BRCA1 BRCA tumor formation, as well as suggesting a genotype based gene. A haplotype was found with a high frequency associated method for choosing different treatment strategies for breast with these mutations in the general population [63]. The carcinoma in women with BRCA mutations [51]. presence of such founder mutations had direct application in genetic testing. VII. ALLELIC VARIANTS OF BRCA1 & BRCA2GENES IX. PATHOLOGY AND ALLELIC VARIANTS OF BREAST CANCER BRCA1 and 2 genes acts as tumor suppressor genes, when there is loss of the unaltered allele of genes [52, 53]. Women with The phenotype for BRCA related tumors appeared to be mutation in one of the two genes i.e. BRCA1 & 2. The allele has heterogeneous, and is better described in BRCA1 as compared a high risk of breast cancer development [54]. The pathology of to BRCA2 [64]. The pathological features of breast cancer in BRCA gene allelic variants can lead to differential function of women with BRCA1, mutations showed a number of high grade the proteins, DNA repair or transcriptional activity. tumors, lack of in situ ductal carcinoma, high mitotic rates, high Accumulation of the side effects could results in chromosomal rate of aneuploidy, lacking estrogen receptor-negative and high instability which may cause carcinoma formation. frequency of great intensity immunostaining of p53 [65]. Mutations in BRCA1 & 2, give a highly increased susceptibility X. GENETIC COUNSELING to breast cancers. The current scenario is that these are also The genetic counseling is an important part of any cancer known as caretaker genes. Upon removal of these genes other genetic testing study. This is basically a management program, genetic disorders may accumulate. Nature of these biological taking place before exact analysis of FNAC or pathogenetic events can define the path by which BRCA1 & 2 function. studies. The consent should be obtained from patients so that Nearly two thousand different sequence variants in BRCA1 &2 protection of confidentiality will ‘secure according to the have already been reported. The mutation pattern is very regulations of the health insurance, portability & accountability complicated and heterogeneous. CGCIJCTR2019 www.cgcijctr.com Page 50 © All Rights Reserved to CGCIJCTR CGC International Journal of Contemporary Technology & Research ISSN: 2582-0486 (online), Vol.-2, Issue -1 DOI: 10.46860/cgcijctr/2019.12.30.48 act [66]. Patients should be fully informed about the different [13]. Li FP, Fraumeni JF.1969, Soft-tissue sarcomas,breast cancer faceted issues related with genetic testing. In case of hereditary and other neoplasms.A familial syndrome? Ann. Intern. Med; breast ovarian cancer (HBOC) syndrome, the patient must be 71 :747-752. fully apprised of the fact that failure to identify a BRCA1 or [14]. Anderson DE.1971, Some characteristics of familial breast cancer Cancer;28:1500-1504. 2mutation in the family does not exclude the presence of [15]. Lynch HT, Krush AJ, Guirgis H. 1973, Geneticfactors in hereditary factors [4]. The remainder of HBOC cases would be families with combined gastrointestinal and breastcancer. due to identified alterations [6]. The high risk patients must also Am. J. Gastroenterol; 59:31-40. be appreciated the fact that BRCA mutations are not exactly [16]. Fraumeni JF, Grundy GW, Creagan ET, Everson RB.1975, penetrant. Six families prone to ovarian cancer.Cancer; 36:364-369. [17]. Anderson DE.1974, Genetic study of breast cancer- XI. CONCLUSION Identification of a high risk group. Cancer 34:1090-1097. This review covered the knowledge of reproductive factors and [18]. Langlands AO, Kerr GR, Bloomer S. 1976, Familial breast cancer.Clin.Oncol; 2:41-45, human genetics facts which are important for the diagnosis and [19]. Cady B.1970, Familial bilateral cancer of the breast.AnnSurg; analysis of most forms of hereditary breast carcinoma, 172:264-272. particularly the hereditary breast cancer syndromes. A large [20]. Kessler HJ, Grier RN, SeidmanI, McIlveenSJ.1976, Bilateral number of studies have pointed out the role of heredity, primary breast cancer.JAMA; 236:278-280. reproductive risk factors, genetic contributions in different genes [21]. Bain C, Speizer FE, Rosner B, Belanger C,Hennekens CH. like BRCA1 & 2related with breast cancer risk. However, due to 1980, Family history of breast cancer asa risk indicator for limited knowledge on family history in the etiological studies of the disease. Am J Epidemiol;111:301-318. breast cancer, its role is not fully understood. There is need of [22]. Willett WC, Hunter DJ, Stampfer MJ.1992, Dietary fat and best expertise physician who examine the patients carefully and fiber in relation to risk of breastcancer: an 8-year follow-up. JAMA.;268:2037-2044. recommend regular clinical breast cancer examination and [23]. Floderus B, Barlow L, Mack TM. 1990, Recall bias mammography for all women over the age of 50 years, for both insubjective reports of familial cancer.Epidemiology.;1:318- those with and without a family history of breast cancer. 321. [24]. London SJ, Colditz GA, Stampfer MJ.1989,Aprospective study of relative weight, height, and the risk of breast cancer. REFERENCES JAMA;262:2853-2858. [25]. Colditz GA, Stampfer MJ, Willett WC.1987, Reproducibility [1]. Colditz GA, Willett WC, Hunter DJ, Stampfer MJ, Manson and validity of self-reported menopausalstatus in a JE.1993, Family history, age, and risk of breast cancer: prospective cohort ofwomen. AmJ Epidemiol.; 126:319-325. prospective data from the Nurses' Health Study. Jama.; [26]. Cox DR. 1972, Regression models and life-tables. JR Stat 270(3):338-43. Soc;34(series B):187-220. [2]. Vassilarou D, Tzonou A, Vassilaros S, Kalandidi A.1990, [27]. Stampfer MJ, Willett WC, Speizer FE.1984, Test of the Familial occurrence of breast cancer in a population with National Death Index. Am J Epidemiol;119:837-839. intermediate disease rates: a study in Greece. Cancer J; 3:244- [28]. Sellers TA, Kushi LH, Potter JD.1992,Effectof family 247. history, body-fat distribution, and reproductivefactors on the [3]. Roseman DL, Straus AK, Shorey W. 1990, A positive family risk ofpostmenopausal breast cancer. N Engl J history of breast cancer: does its effect diminish with age? Med;326:1323-1329. Arch Intern Med;150:191-194. [29]. Houlston RS, McCaiter E, Parbhoo S, ScurrJH, Slack J. 1992, [4]. Lynch HT, Snyder CL, Lynch JF, Riley BD, Rubinstein WS. Family history and risk of breast cancer. J Med Genet;29:154- 2003, Hereditary breast-ovarian cancer at the bedside: role of 157. the medical oncologist. J ClinOncol;21:740–53. [30]. Iselius L, Slack J, Littler M, Morton NE. 1991, [5]. Dıez O, Osorio A, Dura´n M. 2003, Analysis of BRCA1 and Geneticepidemiology of breast cancer in Britain. Ann Hum BRCA2 genes in Spanish breast ovarian cancer patients: A Genet;55:154-159. high proportion of mutations unique to Spain and evidence of [31]. King M-C, Rowell S, Love SM. Inherited breastand ovarian founder effects. Hum Mutat;22:301–12. cancer: what are the risks? whatarethe choices? JAMA. [6]. Walsh T, Casadei S, Coats KH. 2006, Spectrum of mutations 1993;269:1975-1980. in BRCA1, BRCA2, CHEK2, and TP53 in families at high [32]. Ottman R, Pike MC, King M-C, CasagrandeJT,Henderson risk of breast cancer. JAMA;295:1379–88. BE. 1986, Family breast cancer in a population- based series. [7]. Huusko P, Juo SH, Gillanders E.2004, Genome-wide Am J Epidemiol;123:15-21. scanning for linkage in Finnish breast cancer families.Eur J [33]. Hall JM, Lee MK, Newman B. 1990, Linkage of early-onset Hum Genet;12:98–104. familialbreast cancer to chromosome 17q21. Science; 250: [8]. Smith P, McGuffog L, Easton DF.2006, A genome wide 1684–1689. linkage search for breast cancer susceptibility genes. Genes [34]. Hopper JL. 2001, More breast cancer genes? Breast Cancer Chromosomes Cancer;45:646–55. Res; 3:154–157. [9]. Easton DF, Pooley KA, Dunning AM.2007, Genome-wide [35]. Garber JE, Goldstein AM, Kantor AF.1991, Follow-up study association study identifies novel breast cancer susceptibility oftwenty-four families with Li–Fraumeni syndrome. Cancer loci. Nature;447:1087–93. Res;51: 6094–6097 [10]. Mersheimer WL, Dursi JF. Familial [36]. Lindor NM, Greene MH. 1998, The concise handbook of cancersusceptibility.1971, Rev. Surg; 28:316-321. family cancersyndromes. Familial Cancer Program. J Natl [11]. Finney G G, Finney GG, Montague AC, Brown CC. 1972, Cancer Inst; 90:1039–1071. Bilateral breastcancer, clinical and pathological review. Ann. [37]. Bell DW, Varley JM, Szydlo TE.1999, Heterozygous germ Surg; 175:635-646. linehCHK2 mutations in Li–Fraumeni syndrome. Science; [12]. Mintz U, Amir J, De Vries A. Familial breastcancer.1974, 286:2528–2531 Rev. Roum.Mid; 12:13-14. [38]. Savitsky K, Bar-Shira A, Gilad S.1995,A single ataxia CGCIJCTR2019 www.cgcijctr.com Page 51 © All Rights Reserved to CGCIJCTR CGC International Journal of Contemporary Technology & Research ISSN: 2582-0486 (online), Vol.-2, Issue -1 DOI: 10.46860/cgcijctr/2019.12.30.48 telangiectasiagene with a product similar to PI-3 kinase. effects among Dutchand Belgian hereditary breast and Science; 268:1749–1753. ovarian cancer families. Am J Hum Genet; 60: 1041–1049. [39]. Telatar M, Teraoka S, Wang Z.1998, Ataxia-telangiectasia: [60]. Einbeigi Z, Bergman A, KindblomLG. 2001, A founder identificationand detection of founder-effect mutations in the mutation of the BRCA1 gene in Western Sweden associated ATM gene inethnic populations. Am J Hum Genet; 62: 86– with a high incidence of breast and ovarian cancer. Eur J 97. Cancer; 37: 1904–1909. [40]. Olsen JH, Hahnemann JM, Børresen-Dale AL.2001, Cancer [61]. Pisano M, Cossu A, Persico I.2000, Identification of a inpatients with ataxia-telangiectasia and in their relatives in founder BRCA2 mutation in Sardinia. Br J Cancer; 82: 553– the Nordic countries. J Natl Cancer Inst; 93: 121–127. 559. [41]. Jenne DE, Reimann H, Nezu J.1998,Peutz–Jeghers syndrome [62]. Baudi F, Quaresima B, Grandinetti C.2001, Evidence of a iscaused by mutations in a novel serine threonine kinase. Nat founder mutation of BRCA1 in a highly homogeneous Genet; 18: 38–43. population from southern Italy with breast/ovarian cancer. [42]. Westerman AM, Entius MM, Boor PP.1999,Novel mutations Hum Mutat; 18:163–164. in theLKB1/STK11 gene in Dutch Peutz–Jeghers families. [63]. Caligo MA, Ghimenti C, Cipollini G.1996, BRCA1 germline Hum Mutat; 13: 476–481. mutational spectrum in Italian families from Tuscany: a high [43]. Giardiello FM, Brensinger JD, Tersmette AC. 2000, Very frequency of novel mutations. Oncogene; 13: 1483–1488. high risk ofcancer in familial Peutz–Jeghers syndrome. [64]. Phillips KA. 2000, Immunophenotypic and pathologic Gastroenterology;119: 1447–1453. differences between BRCA1 and BRCA2 herditary breast [44]. Chen Y, Farmer AA, Chen C.1996, BRCA1 is a 220 kDa cancers. J ClinOnco; 18: 107S–112S. nuclear phosphoprotein that is expressed and phosphorylated [65]. Lakhani SR, Van De Vijver MJ, Jacquemier J.2002, The in a cell cycledependentmanner. Cancer Res; 56: 3168–3172. pathology of familial breast cancer: predictive value of [45]. Bertwistle D, Swift S, Marston NJ.1997,Nuclear location and immunohistochemical markers estrogen receptor, cell cycle regulation of the BRCA2 protein. Cancer Res; 57: progesterone receptor, HER-2, and p53 in patients with 5485–5488. mutations in BRCA1 and BRCA2. J ClinOncol; 20: 2310– [46]. Callebaut I, Mornon JP. 1997, From BRCA1 to RAP1: a 2318. widespread BRCT module closely associated with DNA [66]. U.S.Department of Health and Human Services repair. FEBS Lett; 400: 25–30. (USDHHS).HIPAA-General Information.U.S.Department of [47]. Venkitaraman AR. 2002, Cancer susceptibility and the Health and Human Services, 2005. functions of BRCA1 and BRCA2. Cell; 108: 171–182. [48]. Kubista M, Rosner M, Miloloza A. 2002, BRCA1 and differentiation. Mutat Res; 512: 165–172. [49]. Zheng L, Li S, Boyer TG, Lee WH.2000, Lessons learned from BRCA1 and BRCA2. Oncogene; 19: 6159–6175. [50]. Thompson D, Szabo CI, Mangion J. 2002, Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. ProcNatlAcadSci USA; 99: 827–831. [51]. Perez Mdel R, Dubner D, Michelin S.2002, Telomeres and genomic damage repair. Their implication in human pathology.Medicina; 62: 593–603. [52]. Collins N, McManus R, Wooster R.1995, Consistent loss of the wild type allele in breast cancers from a family linked to the BRCA2 gene on chromosome 13q12-13. Oncogene; 10: 1673–1675. [53]. Holt JT, Thompson ME, SzaboC.1996, Growth retardation and tumour inhibition by BRCA1. Nat Genet; 12: 298–302. [54]. Antoniou A, Pharoah PD, Narod S. 2003, Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet; 72: 1117–1130. [55]. Malone KE, Daling JR, Thompson JD. 1998, BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA; 279: 922–929. [56]. Risch HA, McLaughlin JR, Cole DE.2001, Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet; 68: 700–710. [57]. Struewing JP, Hartge P, Wacholder S et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med; 336: 1401–1408. [58]. Ellisen LW, Haber DA. 1998, Hereditary breast cancer.Annu Rev Med; 49: 425–436. [59]. Peelen T, van Vliet M, Petrij-Bosch A.1997, A high proportion ofnovel mutations in BRCA1 with strong founder CGCIJCTR2019 www.cgcijctr.com Page 52 © All Rights Reserved to CGCIJCTR