Hereditary Genes and SNPs Associated with Breast Cancer

Breast cancer is a complex disease that is caused by abnormal growth and uncontrolled division of cells within the terminal duct and lobular of the breast. It mainly occurs in women and less commonly in men. The majority of breast cancers are sporadic in origin and an appreciable fraction is caused by inherited predisposition (Collaborative Group on Hormonal Factors in Breast Cancer, 1996). Breast cancer, with approximately one million new patients in each year, is the most common malignancy among women (Coley, 2008). Breast cancer is included about 10 percent of all cancers and 23 percent of women cancers in developed countries (Coley, 2008). Over 15% of healthy women have at least one first-degree relative with breast cancer and experimental data showed that the risk of breast cancer in women has been doubled in recent years (Robson et al., 2007). Breast cancer is the second killer cancer among American women after lung cancer (http://www.wwhf. org/hi_cancer_4.asp). Researches have shown that women with a family history of breast cancer have increased risk of developing breast cancer. The mutations responsible for increasing breast cancer risk within families are recognized. These include mutations in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS1, PMS2, PTEN, RAD50, RAD51C, STK11 and TP53 genes. These rare mutations are probably assigned to a small percent (2-5%) of breast cancer cases (http://www.snpedia.com/


Introduction
Breast cancer is a complex disease that is caused by abnormal growth and uncontrolled division of cells within the terminal duct and lobular of the breast.It mainly occurs in women and less commonly in men.The majority of breast cancers are sporadic in origin and an appreciable fraction is caused by inherited predisposition (Collaborative Group on Hormonal Factors in Breast Cancer, 1996).Breast cancer, with approximately one million new patients in each year, is the most common malignancy among women (Coley, 2008).Breast cancer is included about 10 percent of all cancers and 23 percent of women cancers in developed countries (Coley, 2008).Over 15% of healthy women have at least one first-degree relative with breast cancer and experimental data showed that the risk of breast cancer in women has been doubled in recent years (Robson et al., 2007).

Single Nucleotide Polymorphisms (SNPs) and Their Importance in Cancer Diagnosis
The occurrence of different forms of an allele in a gene is called polymorphism.Researches have shown that genetic polymorphisms are one of the causes of individual difference in cancer incidence (Karen et al., 2006).In 2001, the complete human genome was sequenced and sequence analyses showed that 99% of genome sequences of different individuals were identical (Sachidanandam et al., 2001).Differences among individuals are due to the existence of 4.5 million single nucleotide polymorphisms distributed throughout the genome in both coding and non coding regions.These polymorphisms are individual different factors in having the unique traits (Chakravarti, 1999).
SNPs are the most common type of genetic variation.SNPs can cause silent, harmless or harmful effects (http:// www.cancer.gov/cancertopics/understandingcancer/geneticvariation/page39).SNPs in the genome can occur in coding and non-coding regions.More SNP occurs in non-coding regions.The researchers concluded that some of the SNPs have a useful activity.If SNP occuring with high frequency near a particular gene, it can be used as a marker for a specific gene, while SNPs occur in coding regions cause change in the produced protein of that gene and the resulting product would have effects on health(http://www.cancer.gov/cancertopics/understandingcancer/geneticvariation/AllPages).Whereas SNPs can act as genetic markers, SNPs profile can aid scientists to identify the complete set of genes that are involved in creating and developing complex diseases like cancer.For example scientists studied SNP profiles of many individuals including cancer patients, and comparison between different profiles made it possible to discover a small subset of SNPs that are present only in cancer patients.As a result, SNPs can be considered as markers for identification of cancer genes.Scientists also use SNPs to estimate the factors contributing to cancer risk in large populations (http://www.cancer.gov/cancertopics/understandingcancer/geneticvariation/AllPages).

Hereditary Genes of Breast Cancer
About 5-10% of breast cancers are thought to be hereditary that are caused by abnormal genes (http:// www.breast cancer.org/risk/factors/genetics).This section describes genes associated with hereditary breast cancer.Some of the most important genes associated with hereditary breast cancer and their characterizations are given in the Table 1.

Breast cancer susceptibility gene 1 and breast cancer susceptibility gene
Known genetic factors that are important in breast cancer include high-risk mutations in Breast Cancer susceptibility gene 1 (BRCA1) and Breast Cancer susceptibility gene 2 (BRCA2) genes (http://www.23andme.com).Mutations in BRCA1 and BRCA2 genes in germline cells cause susceptibility to breast and ovarian cancer.BRCA1 gene is considered as one of the breast cancer genes.The majority mutations of BRCA1 are nonsense mutations that they are a major part of the known mutations.The high frequency of this type of mutation showed that when the gene product is defective, it will lose its performance and this process will lead to cancer (Ahn et al., 2007).Mutated BRCA1 gene and less likely BRCA2 gene increases ovarian cancer risk.BRCA2 mutation in male breast cancer has been observed more than BRCA1 mutation.Female carriers of BRCA1 and BRCA2 mutations are predisposed to high lifetime risk of breast cancer.Mutation in BRCA1 and BRCA2 gene in females also increased the risk of pancreatic cancer and other cancers, while in males it increased the risk of prostate cancer, pancreas cancer and breast cancer (Thompson et al., 2005).
There are specific mutations to particular areas of the BRCA1 gene in breast cancer.Such mutations which can be mentioned include exon 2 mutations in Ashkenazi Jewish descent (http://www.cancer.gov/cancertopics/understandingcancer/geneticvariation/page39), mutation in exon 13 of African -American descent (Pal et al., 2004), mutation in exon 7 and 11 in Hindi women (Valarmathi et al., 2002) and mutation in exon 11 in region of North America (Liede et al., 2002).BRCA1 and BRCA2 genes play an important role in DNA repair by homologous recombination, maintain chromosome stability, activation of DNA damage control points and regulation of cell cycle (Ahn et al., 2007).

Chekpoint kinase 2
Chekpoint kinase 2 (CHEK2) encodes a G2 checkpoint kinase which is involved in DNA damage repair.Previous studies have demonstrated that mutations in CHEK2 gene increase breast cancer risk, particularly among women with a family history of breast cancer.The risk of breast cancer may be higher for women who have both a CHEK2 gene mutation and a family history of breast cancer (Cybulski et al., 2011).The reports indicated that faulty of CHEK2 gene, called CHEK2*1100delC, was more common in women prognosticated with breast cancer than in healthy women (The CHEK2 Breast Cancer Case-Control Consortium, 2004).CHEK2 1100delC gene mutation is one of the most common genetic mutation associated with breast cancer.The risk of CHEK2 1100delC gene mutation is higher in women with a family history of the disease and it is estimated that women with one copy of this mutation have at least twice the risk of breast cancer (http://www.23andme.com).One of other CHEK2 variants that have been associated with breast cancer risk is I157T (470T>C) variant in the FHA domain in exon 3. The IVS2+1G>A splicing mutation that is found in the US, Polish, and German patients with familial prostate cancer showed associates possibly with a 2-4 fold evaluated risk for breast cancer.Also studies have reported that mutations in this gene are associated with ovarian, lung, prostate, colon, kidney and thyroid cancers (http://ghr.nlm.nih.gov/gene).

Phosphate and tensin homolog
Phosphate and Tensin homolog (PTEN) is one of the most important tumor suppressor genes that is associated with risk of breast cancer.PTEN protein helps regulate the cycle of cell division and cell growth (http://ghr.nlm.nih.gov/gene).PTEN gene may function as tumor suppressors due to the ability to counteract the action of kinases.Mutation and deletions in the PTEN gene are reported at high frequency in breast, brain, prostate and kidney cancer (Gang et al., 2002).The effect of PTEN gene mutations is controversial in the beginning of breast cancer.Germline mutations of PTEN gene cause Cowden syndrome and hamartoma.PTEN c. 697C>T (R233*) mutation causes in the introduction of premature stop codon into the PTEN gene and occurs in exon 7, which encodes a portion of the C2 domain and is associated with breast cancer (http://www.mycancergenome.org/content/disease/breast-cancer/PTEN/25).

Tumor Protein 53
Tumor Protein 53 (TP53) gene is one of the most important tumor suppressor genes.The risk of developing breast cancer increases with changes in the TP53 gene.This gene has a key role in the maintenance of genome integrity and prevents the proliferation of cells with damaged DNA.Thus it plays a role in the inactivation of tumor-causing genes.About 40% of cases of breast carcinoma have mutated form of TP53 gene (Barnes and Camplejohn, 1996).Mutations in TP53 gene lead to unregulated cell growth and division (http://ghr.nlm.nih.gov/gene).One copy of the TP53 gene is lost in some cases of breast cancer and the remaining copy which has a mutation, thus prevents the production of any tumor protein 53 in the cell and leads to a cancerous tumor.Several polymorphisms and their possible roles in breast cancer risk have been detected in the TP53 gene (http:// ghr.nlm.nih.gov/gene).

Ataxia Telangiectasia Mutated
Ataxia Telangiectasia Mutated (ATM) gene may be associated with an increased risk of breast cancer.The role of the ATM gene is controlling cell division.Reports have shown that having a mutation in one copy of the ATM gene in each cell increased the risk of developing breast cancer and ATM protein is half the normal amount in cells that are missing one of the ATM gene (http://ghr.nlm.nih.gov/gene).Missense mutations may be responsible for the majority of breast cancer occuring among ATM heterozygotes.The prevalence of ATM variants varies among different populations.7271T>G and IVS10-6T>G mutations in ATM gene have shown that they are associated with a sufficiently high risk of breast cancer (http://ghr.nlm.nih.gov/gene).

ER-α and ER-β genes
Estrogen has been shown to contribute to the development and progression of breast cancer risk through its metabolites and have been reported that polymorphisms in estrogen receptor gene Estrogen receptor-α (ER-α) and Estrogen receptor-β (ER-β) act as modifiers of breast cancer risk and are associated with the increased risk of breast cancer in women (Schiff et al., 2004).ER-α and ER-β are located on chromosomes 6q25.1 and 14q22-24 in human respectively (Hosseini, 2011).Some of the studies suggested that alterations in ER-α and ER-β occur during breast cancer development.The human ER-α gene has been shown to have a low mutational frequency in breast cancer tissue (Roodi et al., 1995).

PR-A and PR-B genes
Progesterone hormone regulates ovulation and is responsible for pregnancy associated proliferation and differentiation of breast and endometrium.The progesterone receptor gene (PR) is located on 11q22-23 and encoded receptor protein.The PR gene is transcribed from two alternative promoters and translated into different zinc-finger protein Progestron receptor-A (PR-A) and Progestron receptor-B (PR-B).There are variants that alter function and or expression of the PR gene (Karen et al., 2006).

SNPs associated with breast cancer
Several recent studies reported genes involved in DNA repair and SNPs associated with increased risk of breast cancer.Access to candidate genes indicated that the average risk of breast cancer for rare mutations in genes involved in DNA repair (PALB2, BRIP1, CHEK2, ATM and RAD50) has increased.Genome Wide Association Study (GWAS) has identified SNPs as low-percent breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known gene (LSP1, TOX3, FGFR2, TGFB1, MAP3K1, 2q35 and 8q) (Ahmed et al., 2007).Specific hereditary breast cancerassociated mutations are found in people with Ashkenazi Jewish ancestry.These mutations account for 80-90% of hereditary breast cancer and ovarian cancer cases in this ethnic group.These SNPs include 185delAG and 5382insC in the the BRCA1 gene and 6174delT in the BRCA2 gene (Nechushtan et al., 2009).A recent metaanalysis estimated that women with either the 185delAG or 5382insC BRCA1 mutation have approximately 60% risk of developing breast cancer by age 70 and for women with the 6174delT BRCA2 mutation estimated risk of breast cancer is about 50% by age 70.These mutations increased the risk of breast cancer in men.Risk of breast cancer estimated at 6.9% at the age 80 for males with a BRCA2 mutation (Mendel, 2012).Fiuji (2011) studied the frequency of the 5382insC (rs76171189) mutation of the BRCA1 gene by ARMS-PCR in 100 Iranian breast cancer patients in Mashhad.Control samples were selected from 30 healthy women.They reported a significant correlation between5382inscC (rs76171189) mutation and breast cancer and reported that there is a high frequency of 5382inscC mutation among Iranian people who are suffering from breast cancer (Fiuji, 2011).Also Fiuji et al. (2011) investigated the frequency of the 18delAG mutation of the BRCA1 gene by ARMS-PCR in 100 Iranian breast cancer patients in Mashhad.Results showed a high frequency of 18delAG mutation among Iranian people who are suffering from breast cancer (Fiuji et al., 2011).Fiuji et al. (2011) designed and produced kits for identification of mutations 5382insC and 185delAG of BRCA1 gene by ARMS-PCR method (Fiuji et al., 2011a;2011b) Johnson et al. ( 2007) studied 1,037 potentially functional SNPs in 437 women with two primary breast cancer and 2,463 controls.Their results showed that twenty five of these SNPs in the BRCA1, BRCA2, ATM, TP53 and CHEK2 genes were associated with breast cancer.SNPs that had risk allele for breast cancer included SNPs of the BRCA1 gene (rs1799950, rs4986850, rs22279945, rs16942, and rs1799966), SNPs of the BRCA2 gene (rs766173, rs144848, rs4987117, rs1799954, rs11571746, rs11571747, rs4987047, rs11571833 and rs1801426), SNPs of the ATM gene (rs3218707, rs4987945, rs4986761, rs3218695, rs1800056, rs1800057, rs3092856, rs1800058 and rs1801673), SNPs of the CHEK2 gene (rs1787991) and SNPs of the TP53 gene (rs1042522) (Johnson et al., 2007).Cox et al. (2007) genotyped nine SNPs that based on prior evidence had reported association with breast cancer.They used datasets that include 11391-18290 patient cases and 14753-22670 controls from 9-15 studies and found evidence from an association with breast cancer for CASP8 D302H (rs1045485) with odds ratios of 0.89 and 0.74 for heterozygotes and rare homozygotes, respectively, and weaker for TGFB1 L10P (rs1982073) with odds ratios of 1.07 and 1.16 for heterozygotes and rare homozygotes, respectively (Cox et al., 2007).Stacey et al. (2007) genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls.They reported rs13387042 on chromosome 2q35 and rs3803662 on chromosome 16q12 associated with breast cancer (Stacey et al., 2007).Antonis et al. (2007) studied SNP in the 5 'UTR of the gene RAD51 (135 GgC) that based on prior evidence was reported as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers and observed evidence of an increased breast cancer risk in CC homozygotes.They analyzed BRCA1 and BRCA2 mutation carriers separately and reported cancer risk statistically significant only for BRCA2 mutation carriers.They concluded that 135 GgC may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51 (Antonis et al., 2007).Ahmed et al. (2009) carried out a Genome Wide Association Study for breast cancer susceptibility loci in two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS Collaboration and Breast Cancer Association Consortium and reported strong evidence for susceptibility loci on 3p (rs4973768) and 17q (rs6504950) that are associated with breast cancer (Ahmed et al., 2009).Zheng et al. (2009) carried out a Genome Wide Association Study in order to identify risk variants for breast cancer among Chinese women and analyzed 607728 SNPs in 1505 cases and 1522 controls.They reported that SNP rs2046210 at 6q25.1 located upstream of the gene encoding estrogen receptor α, showed strong association with breast cancer (Zheng et al., 2009).Nechushtan et al. (2009) investigated a germline single nucleotide polymorphism in the first intron of the gene encoding MDM2 at position 309, an important modular of P53.Then they studied 453 Ashkenazi breast cancer patients of which 180 patients were positive for BRCA1/2 mutations.They reported that MDM2SNP309G/C main effect on BRCA1/2 mutation carriers is linked to its effect on patient survival Nechushtan et al., 2009).Thomas et al. ( 2010) carried out a three-stage Genome Wide Association Study of breast cancer in 9,770 cases and 10,799 controls and two new SNPs were identified.The first SNP was on chromosome 1p11.2(rs11249433) and the second one was on chromosome 14q24.1 (rs999737).They also reported associations with loci on chromosome 5p12, 2q35, 8q24, 10q26, 5q11.2 and 16q12.1 (Thomas et al., 2010).Fu et al. ( 2010) investigated SNP rs11249433 in the 1p11.2region that was previously identified as a novel genetic risk factor for breast cancer and the association was in patients with estrogen receptor (ER+) versus ER-cancer.They reported association between SNP rs11249433 and expression of the NOTCH2 gene in the 1p11.2region and showed that the expression of NOTCH2 differed in subgroups of breast tumors and by genotypes of the breast cancer associated SNP rs11249433 (Fu et al., 2010).Zhang et al. (2008) genotyped polymorphisms in the regulatory regions of ER-α gene (rs3798577) among 300 breast cancer cases and 390 controls in a Chinese population and they identified that the TT allele frequency of ER-α was significantly higher in cases than controls (Zhang et al., 2008).Abbasi et al. (2012) scanned variants of the ER-α and ER-β genes in 150 Iranian patients and control individuals by SSCP method and reported three SNPs in codon 10 (TCTgTCC), codon 325 (CCGgCCC) and codon 594 (ACGgACA) in ER-α gene and one SNP in codon 392 (CTCgCTG) of ER-β gene that have additive effects in developing breast cancer.They also revealed that SNP in codon 392 of ER-β is more effective than SNPs in codons 10, 325 and 594 of ER-α gene in developing LN metastases in breast cancer patients (Abbasi et al., 2012).Also Hosseini, (2010) investigated expression of ERα and ERβ gene in cancer tissues and reported that higher expression of ERα gene and lower expression of ERβ gene in cancer tissues can be important factors in the breast cancer development (Hosseini , 2010).
There are variants that alter function and/or expression of PR.De Vivo et al. (2002) showed a G to A exchange at position +331 in the promoter region and revealed that this SNP enhances the transcription of PR-B and increases the ratio PR-B to PR-A and has been postulated to predispose women to breast cancer through increasing PR-Bdependent stimulation of mammary cell proliferation (De Vivo et al., 2002).Zabetian et al. (2010) reported that PR-A and PR-B genes can be used as references for identification and screening of cancer patients from healthy persons, even in the first stages of the disease (Zabetian et al., 2010).Cai et al. (2011) conducted a genome wide association study among more than 31,000 DOI:http://dx.doi.org/10.7314/APJCP.2013.14.6.3403Hereditary Genes and SNPs Associated with Breast Cancer women of East-Asian, European, and African ancestry in order to investigate a single nucleotide polymorphism (rs2046210 A/G allele) with breast cancer risk at 6q25.1 position.Their result showed a significant association for rs2046210 and breast cancer risk in Chinese, Japanese and European-ancestry American women for the AG and AA genotypes (Cai et al., 2011).Long et al. (2012) performed a four-stage Genome Wide Association Study to identify novel genetic susceptibility loci for breast cancer in 19,091 cases and 20,606 controls in East-Asian descents including Chinese, Korean, and Japanese women and reported SNP rs9485372, near the TGFgactivated Kinas (TAB2) gene in chromosome 6q25.1 associated with breast cancer risk in the combined analysis of the samples.They also reported SNP rs9383951 located in intron 5 of the ESR1 gene and that SNP rs7107217 located at 11q24.3 were associated with breast cancer risk (Long et al., 2012).
Recently, researches have been focused on SNPs that have statistically significant association with breast cancer risk in the general population such as modifiers of risk in BRCA1 and BRCA2 mutation carriers.These genetic modifiers for carriers of mutations in BRCA1 and BRCA2 have been identified through studies of single nucleotide polymorphism (SNPs) in candidate genes and genome wide association study (GWAS) includes: D302H of CASP8 (Engel et al., 2010), rs2981522 of FGFR2, rs3803662 of TOX3/TNRC9, rs889312 of MAP3K1 (Antoniou et al., 2010), rs3817198 of LSP1, rs13387042 of 2q35 and rs13281615 of 8q24 (Garcia-Closas., 2008).Also several loci have been indicated in which the occurrence of SNPs is associated with breast cancer risk in the general population.Some of these loci identified in the general population are shown in Table 2

Electronic Databases That Study SNPs in Breast Cancer
There are databases that study SNPs in breast cancer.Some of the databases are shown in

Table 3
Conclusions

Table 3 . Large Web Databases for SNP Associated with Breast Cancer
/hapmap.ncbi.nlm.nih.gov/genetic variation.HapMap is a key resource for researchers to find genetic variants affecting health, disease and responses to drugs and environmental factors

Table 2 . SNPs Associated with Breast Cancer in the General Population
Antonis et al., 2007progeny.Therefore, SNPs of genes associated with breast cancer are used as a potential tool for improving cancer diagnosis and treatment planning.Recently, the cost and time of sequencing are reduced and it provides to screen all genes associated with breast cancer risk and suggests that developing a screening test for known mutations.Therefore, in the near future low cost of nextgeneration whole genome sequencing and high throughput technologies allow to discovery SNPs that associated with breast cancer and can do screening programs on the basis of genetic information in order to reduce morality associated with breast cancer.Also, developing knowledge of the mutations, role in breast cancer susceptibility allows the explanation of breast cancer risk in individual family members and risk level appropriate screening and risk management confirmations.