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Role of Genetic Polymorphisms in Breast
Cancer
6
Mohammad Rafiq Wani
Abstract
Of all cancers that affect women, the highest number of deaths results from breast
cancer (BC). The tumorigenesis of BC is due to either chromosomal instability
(CIN) or genetic polymorphisms of various genes involved in varied cellular
processes. Numerous single-nucleotide polymorphisms (SNPs) have been
identified and associated with an increased risk of BC. Some of these SNPs are
considered potential markers of BC and thus are important for early diagnosis and
personalized targeted therapy of BC. The present chapter summarizes the SNPs of
various genes and their association with breast cancer.
Keywords
Breast cancer · Polymorphism · DNA repair · Cyclins · Xenobiotic metabolism
Abbreviations
BC Breast cancer
BER Base excision repair
HER2 Human epidermal growth factor receptor 2
HR Hormone receptor
IDC Invasive ductal carcinoma
MMR Mismatch repair
NER Nucleotide excision repair
PI3K Phosphatidylinositol-3 kinase
M. R. Wani (*)
Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh, Uttar Pradesh,
India
#
The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2021
A. S. Sameer et al. (eds.), Genetic Polymorphism and Cancer Susceptibility,
https://doi.org/10.1007/978-981-33-6699-2_6
165
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SNP Single-nucleotide polymorphism
TGF Transforming growth factor
VDR Vitamin D receptor
6.1 Introduction
Of all cancers affecting women, breast cancer (BC) ranks first in mortality rate (Bray
et al. 2018). As per WHO, BC killed over half-a-million women in 2018 worldwide.
Even though BC is prevalent in developed countries, in recent years, developing
countries have also witnessed an increasing trend in the number of BC cases.
Breast cancer originates when breast cells divide uncontrollably, forming a small
mass or lump initially in the lobules of the breast or in the ducts connecting nipple to
lobules. This initial small mass can grow, invade nearby tissues such as lymph
nodes, and can even spread to organs outside the breast through blood. Proliferation
of fibrous tissue is commonly seen in most cases of breast cancer and the tissues
around the proliferation site contract, causi ng skin dimpling and inward-drawing of
the nipple area (Catterall 1995; Bundred and Downey 1996).
For a better prognosis and prevention of BC, early diagnosis is required which is
possible through genetic testing. BRCA1 and BRCA2 are two genes often tested in
breast cancer as it has been confirmed that mutations in these two genes increase the
risk of BC. However, these mutations tend to be prevalent in only 0.2–0.3% of the
general population, which can go up to 20% in BC patients (Nelson et al. 2013). This
low overall prevalence limits their use; so, other potential genetic markers need to be
explored. Research studies have confirmed that variants of certain genes resulting
from genetic polymorphisms could increase the risk of developing BC; thus, the
genetic polymorphisms can be used as potential markers of BC (Wendt and
Margolin 2019). Here, we summarize various types of breast cancers, their causes
and symptoms, polymorphisms of genes and their association with breast
cancer risk.
6.1.1 Types
Depending upon the site of origin in the breast, breast cancer is of the following
types:
Ductal carcinoma in situ (DCIS) originates inside the milk ducts but does not
spread into surrounding breast tissue. It is not-lethal and its presence is an indication
that invasive breast cancer can develop in the person later in his life.
Invasive ductal carcinoma (IDC): Majority (80%) of BC cases are IDC type. IDC
is common in women aged 55 years or older. It begins in the walls of the milk duct
and spreads into nearby tissues by breaking through the duct wall and can also
spread outside the breast to other body regions.
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IDC subtypes
• Tubular carcinoma of the breast: These are tube-like structures, usually not more
than 1 cm in size, accounting for about 8–27% of all breast cancers.
• Medullary carcinoma of the breast: These are soft, fleshy mass resembling
medulla of brain, accounting for about 3–5% of all BC cases.
• Mucinous carcinoma of the breast: When observed under a microscope, cancer
cells are scattered, floating in a pool of mucus. This subtype accounts for about
5% of invasive breast cancers and can be diagnosed at any age but usually affects
post-menopausal women.
• Papillary carcinoma: Less than 2% of BCs are papillary carcinoma which is
mostly diagnosed in post-menopausal women.
• Cribriform carcinoma: In this type, cancer spreads to connective tissues with
distinctive holes in between the cancer cells. It is classified as low grade tumor,
one in which BC cells appear like normal breast cells.
Invasive lobular carcinoma (ILC): About 10% of all BCs are ILC type. It refers to
cancer which has spread beyond the lobules into other tissues of the breast.
Inflammatory breast cancer (IBC): It accounts for 1% of all BC cases in the USA,
usually diagnosed in women aged 50–60. The site of origin does not form the usual
lump, but reddens and swells which grows and spreads quickly, with symptoms
worsening each day.
Table 6.1 Estimated new breast cancer cases (DCIS and invasive) and deaths in 2019 among US
women according to age
Age DCIS cases (%) Invasive cases (%) Deaths (%)
<40 2 4 3
40–49 17 14 8
50–59 26 23 18
60–69 30 28 24
70–79 18 20 21
80+ 6 11 27
Source: North American Association of Central Cancer Registries (NAACCR 2019)
Table 6.2 Breast cancer subtypes based on cancer gene expression
Type of breast cancer Category Distribution
a
Luminal A HR+, HER2– 73%
Luminal B HR+, HER2 +/ 11%
Triple-negative/basal-like HR–, HER2– 12%
HER2-enriched HR–, HER2+ 14%
HR hormone receptor (estrogen/progesterone), HER2 human epidermal growth factor receptor 2
a
Distribution of Breast Cancer Subtypes among US Females, 2012–2016. Source: North American
Association of Central Cancer Registries (NAACCR 2019)
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Lobular carcinoma in situ (LCIS): It actually refers to the unusual growth in some
region of breast, usually in women aged 40–50, which may develop into breast
cancer in the future (Tables 6.1 and 6.2).
6.1.2 Classification and Grading
The TNM (tumor, node, metastasis) staging system is commonly used to classify and
grade the tumor (Bundred and Downey 1996) (Table 6.3).
6.1.3 Risk Factors
Several factors referred to as risk factors tend to increase the risk of developing
BC (according to CDC n.d.):
• Sex: BC can develop in women much more frequently than in men.
• Age: Even though there is no particular age for cancer to occur, people in their 50s
have a higher risk than younger people of developing BC.
• A family or personal history of breast cancer/conditions: If a person’s parents,
siblings, or child has BC, there is an increased possibility that the person will
develop BC. However, it must be noted that a vast majority of BC patients have
no familial history of BC.
• Gene mutations: Mutations in certain genes such as BRCA1 and BRCA2 tend to
be associated with hereditary breast cancer.
• Obesity: Breast cancer affects obese people more frequently than people consid-
ered normal weight.
• Beginning period at a younger age: Women whose periods begin before age
12 have higher risk of developing BC than women whose periods begin at
normal age.
Table 6.3 Stages of breast cancer according to TNM classification
TNM Description
5-year
survival
(%)
Stage
I
T
1
,N
0
,M
0
An early-stage BC; tumor <2 cm and localized to the
breast. It can be operable and curable
84
Stage
II
T
1
or T
2
,N
01
or N
1
,M
0
Early-stage BC; tumor <2 cm across and can be found
even in under-arm lymph nodes, or the tumor is 2–5cm
(may or may not be found in lymph nodes), or the tumor
>5 cm and is localized inside the breast
71
Stage
III
T
1–3
,N
2–3
,
M
0
Locally advanced BC; tumor >5 cm across
Cancer has spread to surrounding breast tissue
48
Stage
IV
T
1–3
,N
1–3
,
M
1
Metastatic BC; cancer has spread outside the breast 18
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• Late onset of menopause: Onset of menopause at older age increases the breast
cancer risk.
• Hormone therapy: Women receiving estrogen and progesterone medications
post-menopause as hormone therapy can develop BC.
• Drinking alcohol: Drinking a standard alcoholic drink increases the risk of
developing BC by 7–10%.
Box 6.1: Breast Cancer Patients Generally Show the Following Symptoms
• Appearance of lump in the breast.
• Breast size or shape changes.
• A swelling in breast.
• Irritation in breast skin or pain in any part of breast.
• Discharges such as blood instead of milk from nipple.
6.2 Genetic Background of Breast Cancer
Genome instability is a characteristic of virtually all types of cancer. It can be
grouped into three distinct form s: CIN, MSI, and CIMP pathways. MSI (microsatel-
lite instability) occurs due to expansions and/or contractions of microsatellites (Geigl
et al. 2008; Beckman and Loeb 2005). In CIMP, gene promoters undergo heavy
DNA methylation (CpG dinucleotides), a consequence of which is gene silencing
(Geigl et al. 2008). However, whether these two pathways play any role in breast
cancer is still not clear. In chromosomal instability (CIN), chromosomes or their
parts are lost or gained. CIN changes number of copies of genes, including those
genes whose normal number and function prevent alterations in genome; therefore,
CIN profoundly impacts genome stability (Levine and Holland 2018; Pavelka et al.
2010; Michor et al. 2005). As a result of continuous gains and losses due to CIN, a
set of daughter cells genetically different from their parent cells are produced which
may confer a distinct advantage such as intrinsic drug resistance to the tumor (Lee
et al. 2011) due to which these cells proliferate uncontrollably producing a drug-
resistant tumor (Gerlinger and Swanton 2010).
A study has reported that the lymphocytes isolated from breast cancer patients
have aberrations in certain chromosomes (2, 7, 11, 12, 15, 19, 22, and X) (Guleria
et al. 2005). These regions of the chromosomes harbor various genes that play roles
in genomic stability and breast tumorigenesis. Reports have indicated that BC
patients whose tumors have “extreme” CIN depict better prognosis (Roylance
et al. 2011; Jamal-Hanjani et al. 2017 ). Harsimran et al. (2009) reported that blood
lymphocytes of BC patients have significantly higher number of chromosomal
alterations compared to normal people. Lee et al. (2019) reported a strong positive
correlation between the copy number gain of centromere 17 (CEP1 7) and CIN in
breast cancer, concluding that CEP17 is a useful predictor for CIN in breast cancer.
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6.3 Genetic Polymorphisms in Breast C ancer
Breast cancer patients who otherwise have normal breast tissue histologically have
genetic alterations in their breast cells (Ellsworth et al. 2003). In humans, the most
common variation in the genom e is referred to as single-nucleotide polymorphisms
(SNPs). One person may have T nucleotide at one particular locus, another person
can have any of the remainin g three nucleotides (A, G, or C) at that particular locus.
This is what we call single-nucleotide polymorphism (SNP). Below we report genes
and their polymorphisms that have been associated with the risk of developing BC.
6.3.1 SNPs in DNA Repair Pathway Genes
DNA, the basic unit of inheritance, is highly susceptible to damage by various
intrinsic and extrinsic agents. Further, enzymes involved in DNA replication such
as DNA polymerases are prone to mistakes, inducing undesired and disadvantageous
mutations. Cells invoke their intricate and sophisticated DNA damage response
(DDR) pathways which physically remo ve the damage. Different types of DNA
repair pathways exist in humans that repair different types of DNA damage
(Christmann et al. 2003). Single stranded DNA breaks are usually simple and are
repaired by base or nucleotide excision repair (BER or NER) and mismatch repair
(MMR) (Christmann et al. 2003). Double-strand DNA breaks require complex repair
pathways (Jackson 2002; Pierce et al. 2001).
6.3.1.1 OGG1
OGG1 is an enzyme involved in BER DNA repair pathway. OGG1 (8-oxoguanine
glycosylase) recognizes and cleaves 8-oxo-7,8-dihydroguanine (8-OG) which is the
most common DNA lesion induced during oxidative attack (Nakabeppu 2014).
8-OG is pre-mutagenic, as during DNA replication, it pairs with “A” nucleotide
instead of the usual “C,” the result being G: C-to-T:A transversion (Grollman and
Moriya 1993; Radak and Boldogh 2010).
The human OGG1 gene which encodes the OGG1 glycosylase contains 7 exons
and is located on chromosome 3p26.2. OGG1glycosylase occurs in two isoforms,
a-OGG1 and b-OGG1, which consist of 345 and 424 amino acids, respectively.
Several polymorphisms are present in OGG1 gene including Ser326Cys
(rs1052133) and Gly221Arg (rs373826669), as well as lesser studied SNPs such
as rs55846930, rs1052133. These gene variants, by altering the resultant protein,
may affect OGG1 repair activity as well as susceptibility to various cancers.
Meta-analysis by Ali et al. ( 2015) and Peng et al. (2014) suggested a strong
association of OGG1 SNPs Gly221Arg and Ser326Cys with BC in Asians.
Sangrajrang et al. (2008) suggested a significant association of OGG1 Ser326Cys
SNP with BC among Thai women. Yuan et al. (2010) reported that in European
women, 326Cys allele of OGG1 Ser326Cys SNP confers protection against carcino-
genesis of breast cancer.
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6.3.1.2 RAD51
RAD51 (RAD51 recombinase) is a key protein of homologous recombination
(HR) repair pathway (Richardson 2005) where it mainly functions as a DNA repair
enzyme. It also interacts with BRCA proteins under conditions of oxidative
stress-induced DNA damage and participates in regulating mitochondrial DNA
copy number (Wang et al. 2015).
The human RAD51 gene is present on chromosome 15q15.1. Among many SNPs
of RAD51 gene, G135C (rs1801320) and G172T (rs1801321) have been extensively
studied. Breast cancer patients have reduced RAD51 protein expression and
polymorphisms in RAD51 may be associated with carcinogenesis (Tulbah et al.
2016).
A strong association between BC and RAD51 SNPs (G135C and G172T) has
been observed in many populations of the world (Kadouri et al. 2004; Blasiak et al.
2003; Romanowicz-Makowska et al. 2005;Dufloth et al. 2005; Krupa et al. 2009;
Romanowicz et al. 2010; Ricks-Santi et al. 2011). Numerous meta-analyses have
also focused to elucidate the relation between these two RAD51 genetic variants in
BC among the world populations (Zhao et al. 2014; Gao et al. 2011; Tulbah et al.
2016). Almost all these meta-analysis associated these RAD51 SNPs with the risk
of BC.
6.3.1.3 XPD
XPD is a DNA-dependent ATPase/helicase involved in the NER pathway of DNA
repair (Fan et al. 2002; Benhamou and Sarasin 2002). It excises DNA cross-links,
damaged bases, lesions due to UV and bulky chemical adducts (Flejter et al. 1992;
Coin et al. 1998).
The human XPD gene is present on chromosome 19q13. It has been reported that
polymorphisms in XPD can alter the protein’s repairing ability which may lead to
cancers (Wood et al. 2001; Goode et al. 2002). Two SNPs in XPD gene Asp312Asn
(rs1799793) and Lys751Gln (rs13181) have been extensively studied.
Hussien et al. (2012) reported that XPD Asp312Asn SNP and BC are significantly
associated in an Egyptian population. Lys751Gln SNP enhanced the risk of breast
cancer in XPD-Gln/Gln genotypes (Samson et al. 2011; Smolarz et al. 2019). Wang
et al. (2010) reported that A allele of the XPD Asp312Asn and BC risk share strong
association in Taiwanese patients. A meta-analysis reported that XPDLys751Gln
polymorphism but not XPD Asp312Asn in Caucasians was significantly linked with
BC risk (Yan et al. 2014).
6.3.1.4 XRCC3
The XRCC3 protein takes part in HR repair pathway where it is involved in repair of
chromosomal fragmentation, translocations, and deletions and hence is critical in
maintenance of chromosome stability (Brenneman et al. 2000).
The human XRCC3 gene contains 10 exons and is present on chromosome
14q32.33. Polymorphisms identified in this gene include the well-known XRCC3
Thr241Met (rs861539), A4541G (rs1799794), and A17893G (rs1799796)
6 Role of Genetic Polymorphisms in Breast Cancer 171
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polymorphisms. The polymorphisms may affect the DNA repairing capacity of
XRCC3 protein and contribute to tumor formation (García-Closas et al. 2006).
Ali et al. (2016) reported a significant association of XRCC3 A4541G SNP with
BC in Saudis. Su et al. (2015) associated XRCC3 Thr241Met SNP with BC in the
Taiwanese population. Numerous meta-analyses have focused to explore the relation
between XRCC3 SNP and BC among the world populations (Han et al. 2006;
Economopoulos and Sergentanis 2010; He et al. 2012, 2013). All these meta-
analysis associated Thr241Met SNP with the risk of BC, particularly in Caucasians.
6.3.1.5 hMSH2 Gene
hMSH2 is a component of MMR pathway which repairs mismatches during DNA
replication, thereby maintains the integrity and stability of the genome (Kunkel and
Erie 2005). The MSH2 protein joins MSH6 or MSH3 protein to form a dimer which
identifies errors on the DNA. Then together with MLH1-PMS2 dimer, the MSH2
dimer removes the mismatch (Arshita et al. 2018).
The human MSH2 gene is present on chromosome 2p21-p16.3. Several hMSH2
SNPs have been implicated in numerous cancers including BC (Demokan et al.
2010; Goessl et al. 1997; Hsu et al. 2007; Song et al. 2006). These polymorphisms,
by alternative splicing, lead to altered hMSH2 protein (Beiner et al. 2006; Bubb et al.
1996).
Smolarz et al. (2019) associated hMSH2 Gly322Asp SNP (rs4987188) with a
significant risk of BC (OR ¼ 9.16; 95% CI ¼ 5.57–15.07, p < 0.05). Hsieh et al.
(2017) found a strong link between hMSH2 rs2303425 SNP and BC in a Taiwanese
population. However, a meta-analysis reported that hMSH2 rs2303428 (T > C) SNP
is not significantly associated with BC risk (Wu et al. 2011).
6.3.2 Vitamin D Receptor Gene
Vitamin D may confer protection against many cancers (Bikle 2014; Shao et al.
2012). Vitamin D receptor (VDR) is a 48–55 kD protein found in most human cells.
VDR protein binds with retinoid X receptor, conformationally changing VDR that
allows vitamin D3 to bind at ligand binding domain of VDR.
In humans, VDR gene is present on chromosome 12q13–14 and is 75 kb long
containing 11 exons. More than 470 SNPs have been identified in VDR gene,
including SNPs Fok1 (rs2228570), Bsm1 (rs1544410), Taq1 (rs731236), Apa1
(rs7975232), and Poly A (rs17878969).
Various meta-analysis has reported that there exists no significant association
between BC risk and VDR gene SNPs (Fok1, Bsm1, Taq1, Apa1, and Poly A) both
in mixed races and Caucasian population (Lu et al. 2016; Huang et al. 2014; Xu et al.
2014). However, ff genotype of VDR Fok1 SNP may increase breast cancer risk
(Zhang and Song 2014; Wang et al. 2013a, b; Tang et al. 2009).
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6.3.2.1 BRCA2
BRCA2 protein consists of 3418 amino acids and is known for repairing double
stranded breaks in DNA by homologous recombination (HR). It acts by regulating
another HR protein RAD51 intracellular shuttling and function (Pellegrini et al.
2002).
BRCA2 gene is present on chromosome 13q12.3. Various SNPs have been found
in this gene including the SNP rs144848 located in exon 10 of the BRCA2 gene
(Pharoah et al. 2002). SNP rs144848 (N372H) is an A to C transition that causes an
asparagine-to-histidine substitution (N372H), altering the BRCA2 structure, thereby
affecting its ability to activate the target genes (Fuks et al. 1998). By altering DNA
repair capacity, BRCA2 SNPs may contribute to cancer (Lord and Ashworth 2007).
Meta-analysis done by Faramarzi et al. (2018) reported that among various
BRCA2 SNPs studied, only BRCA2 rs1799955 SNP (S2414S) was found to be
significantly associated with BC. Other meta-analysis reported that BRCA2 N372H
SNP (rs144848) might be associated with BC risk (Li et al. 2017a, b; Qiu et al.
2010a, b).
6.3.2.2 BRCA1
BRCA1 is a multifunctional protein that repairs damaged DNA, regulates cell cycle,
apoptosis, and transcriptional modulation (Venkitaraman 2014). BRCA1 protein
consists of 1863 amino acids and is encoded by BRCA1 gene. Deficient BRCA1
can cause defects in the cell cycle which may lead to cancer development (Deng
2002; Venkitaraman 2002).
BRCA1 gene is present on chromosome 17q2. Various polymorphisms have
been identified in BRCA1 that have been implicated in various cancers, including
breast cancer (Bougie and Weberpals 2011).
Xu et al. (2018) in their meta-analysis reported that in Caucasians,
BRCA1Gln356Arg SNP (rs1799950) decreased the breast cancer risk and
BRCA1Glu1038Gly SNP (rs16941) increased the overall cancer risk. Yang et al.
(2019) reported that BRCA1 SNPs rs799917 (Pro871Leu) and rs1799966
(Ser1613Gly) and BC risk showed no association.
6.3.3 SNPs in Transcription Regulating Genes
6.3.3.1 TP53
TP53 (tumor protein p53) is critical in arresting cell cycle and inducing apoptosis
when DNA is damaged, thereby maintaining the integrity of the genome (Levine
et al. 1991). TP53 is a phosphoprotein of 393 amino acids, having 43.7 kD molecular
weight and is highly rich in proline residues (Fig. 6.1).
In response to stress, ATM and ATR protein kinas es are activated which in turn
activate the p53 protein which binds to DNA causing another gene to produce p21
protein. P21 binds to cell-division promoting cdk2 and inhibits it, thus cell cycle is
arrested. However, mutated p53 does not bind to DNA or binds ineffectively; as a
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result p21 stop signal is not produced and cdk2 is free which promotes cell division
and in the absence of any inhibitor, cell proliferation continues causing cancer.
The p53 gene is present on chromosome 17. It is a tumor suppressor gene and
altered/defective p53 is found in nearly 50% of all cancers (Soussi and Wiman 2007)
and 30% of breast cancers (Olivier et al. 2006). Numerous SNPs in p53 which affect
its function include: intron 3 SNP (rs17878362), intron 4 SNP (rs1794287), and
P47S (rs1800371) (Hu et al. 2010; Bellini et al. 2010; Li et al. 2005). The most
reported polymorphism in p53 is a G/C variation in exon 4 (SNP72; rs1042522),
which causes formation of arginine in place of proline at position 72 (Dahabreh et al.
2013) that markedly affects the primary structure and activity of the protein TP53
(Pim and Banks 2004).
Numerous studies have associated p53 Arg72Pro SNP (rs1042522) with BC
(Bišof et al. 2010; Surekha et al. 2011; Vijayaraman et al. 2012; Pandrangi et al.
2014). P53 rs17878362 SNP, which is an intron 3 16 bp duplication, and BC are
strongly associated (De Vecchi et al. 2008) which is consistent with the results of a
meta-analysis (Hu et al. 2010) (Fig. 6.2).
In a normal cell, as a ligand binds and activates the growth factor receptor, PI3K
is recruited to the membrane through its p85 adaptor subunit, the p110 catalytic
subunit is activated which catalyzes formation of secondary messenger PIP
3
. PIP3
activates serine threonine kinase such as AKT which mediates activates some
downstream target proteins while inhibiting the activity of others, resulting in cell
survival, proliferation, and protein synthesis. Mutated p110 will continue the cell
proliferation resulting in cancer.
Fig. 6.1 Schematic representation of p53 activity
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