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. Author manuscript; available in PMC: 2009 Apr 17.
Published in final edited form as: Curr Treat Options Oncol. 2007 Feb;8(1):61–73. doi: 10.1007/s11864-007-0021-5

New Insights into Breast Cancer Genetics and Impact on Patient Management

Diana S Rosman 1, Virginia Kaklamani 1, Boris Pasche 1,*
PMCID: PMC2670199  NIHMSID: NIHMS89015  PMID: 17634833

Opinion statement

The combined observation that 20–30% of all patients with breast cancer have a family history of the disease and the results from twin studies showing that 25% of breast cancer cases are heritable, indicate that this malignancy is one of the most commonly inherited cancers. Discovery of the BRCA1 and BRCA2 genes more than a decade ago has had a tremendous impact on patient care allowing for early detection and prevention of breast cancer. However, deleterious mutations within the BRCA1 and BRCA2 genes cause at most 3–8% of all breast cancer cases. New data indicate that genomic rearrangements within the same genes may occasionally identify additional carriers of nonfunctional BRCA1 and BRCA2 genes. Such genomic rearrangements are missed by conventional sequencing. The remainder of the unexplained familial risk is presumably due to other yet unidentified high penetrance genes, but polygenic mechanisms and high frequency low penetrance tumor susceptibility genes are likely to account for a greater proportion of familial breast cancers. In this regard, there is growing evidence that a common variant of the type I TGF-β receptor, TGFBR1*6A, may account for approximately 5% of all breast cancer cases, a fraction similar to that attributable to BRCA1 and BRCA2. Such genes may also modify the penetrance of the BRCA1 and BRCA2 genes. In the next decade, screening for combinations of high and low penetrance genes will likely permit the identification of a large fraction of inherited breast cancer cases and will further reduce the burden of familial breast cancer.

Introduction

One in eight women will be diagnosed with breast cancer in her lifetime and it is expected that more than 214,000 new cases will be diagnosed in the U.S. in 2006 [49]. Most cases of breast cancer are sporadic; however, twin studies have shown that heritable factors may cause 20–30% of all breast cancers [35]. While mutations within the BRCA1 and BRCA2 genes are common among women with a strong family history of breast cancer, they account for at most 3–8% of all breast cancer cases. Mutations in the TP53 and PTEN genes, which cause Li-Fraumeni syndrome and Cowden syndrome respectively, are exceedingly rare, and probably account for less than 0.1% of breast cancers. The large effect of heritability in breast cancer suggests major gaps in our knowledge.

Other candidate genes that may cause breast cancer have been identified in the past few years. Cancer susceptibility genes that are associated with an increased risk of breast cancer include TGFBR1*6A, CHEK2*1100delC, and BRIP1 [5,37,41,47]. Many single nucleotide polymorphisms (SNPs) have also been studied and a recent study suggests that 5 of them are associated with breast cancer risk: CASP8 D302H, IGFB3 −202 C>A, PGR V660L, SOD2 V16A, and TGFB1 T29C [Breast Cancer Association Consortium 7]. The respective contribution of these susceptibility genes and candidate SNPs is the focus of several ongoing studies.

These investigations are complicated by the fact that the penetrance of tumor susceptibility genes is highly influenced by other factors such as modifier genes, response to DNA damage, and environmental factors such as exposure to carcinogens, hormonal/reproductive factors, and weight [26].

Genetic testing is currently used to determine if individuals with a personal and/or family history of breast cancer carry mutations or genomic rearrangements within high penetrance breast cancer susceptibility genes. The results of these tests provide useful guidance in deciding how to follow these high risk individuals in order to prevent the occurrence of breast cancer or permit early cancer detection. This article aims to review genes associated with increased breast cancer risk and discuss genetic testing and prevention in individuals with a high risk of developing breast cancer.

High penetrance genes

BRCA1

  • While BRCA1 was cloned more than a decade ago, its exact function is still unknown. This is exemplified by the fact that mice that lack one copy of the Brca1 gene do not exhibit any strong tumor predisposition. However, mice that lack two copies of the Brca1 gene die in utero [14]. These traits have limited in vivo analysis of the Brca1 gene. The BRCA1 protein may not have one specific function, but its interaction with a variety of other proteins is essential for regulating DNA repair, transcription, and cell cycle progression [10].

  • Deleterious mutations within the BRCA1 gene are a frequent cause of breast cancer among women with a strong family history of breast cancer and are associated with a significantly increased risk for the disease. A recent analysis of 22 studies involving 8,139 index case patients unselected for family history shows that carrying a deleterious BRCA1 mutation confers an estimated lifetime risk for developing breast cancer of 65% (95% CI 44–78%) [4]. By the age of 40, carrying a deleterious BRCA1 mutation confers a 20% chance of developing breast cancer, and the risk increases with age, with the lifetime risk being 82% by age 80 [26]. Mutations in BRCA1 are strongly associated with ovarian and fallopian tube cancer [4]. The risk for ovarian cancer for a BRCA1 mutation carrier is 17% by age 40 and increases to 39% by age 70 and 54% by age 80 [4].

BRCA2

  • The BRCA2 gene was also identified a decade ago, one year after BRCA1. The function of BRCA2 is not as ubiquitous as BRCA1. Similarly, to what is observed with Brca1, mice that lack one copy of the Brca2 gene do not exhibit a strong tumor predisposition [14]. Nonetheless, some functional clues have emerged from in vitro studies. After a double strand DNA breaks, BRCA2 induces the translocation of the protein Rad51 into the nucleus and directs Rad51 to the site of the break for homologous recombination-directed repair [56].

  • A smaller fraction of familial breast cancer cases can be attributed to mutations in BRCA2 as compared to BRCA1. In a combined analysis of 22 studies, BRCA2 mutation carriers were found to carry a cumulative breast cancer risk by age 70 of 45% (95% CI = 31% – 56%), and for ovarian cancer of 11% (95% CI = 2.4%–19%) [4].

Reliability of current genetic testing for BRCA1 and BRCA2 deleterious mutations

  • In a study of 300 women who had been diagnosed with invasive breast cancer at any age, had a family history of breast cancer (defined as a family with a minimum of 4 cases of female or male breast cancer, and/or ovarian cancer), and who tested negative for BRCA1 and BRCA2 mutations, as assessed by sequencing of the full coding region of each gene, 35 (11.6%) carried genomic rearrangements within the BRCA1 or the BRCA genes. These mutations were more frequent among individuals under 40 years old [53]. These data strongly suggest that genomic rearrangements within the BRCA1 and BRCA2 genes should be assessed in young probands with a strong family history of breast cancer, especially if the family history also includes male breast cancer and/or ovarian cancer.

TP53

  • TP53 encodes the tumor suppressor protein p53, which inhibits cell cycle progression in the presence of radiation-induced DNA breaks. TP53 mutations are associated with a syndrome named Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFLS) (Table 1).

  • In families with LFS, TP53 is frequently mutated. Studies have shown that although mutations in TP53 are extremely rare in the general population, those with the mutation will develop cancer at some point. In a study of 100 women who had breast cancer, 4 women below 31 years of age had a mutation in TP53, independent of BRCA-gene mutation status; 2/37 familial breast cancer cases had features of LFS or LFLS and 2/63 non-familial cases had mutations in TP53 [32]. In Walsh’s study [53] of 300 women with a strong family history of breast cancer who had neither mutations nor genomic rearrangements within the BRCA1 and BRCA2 genes, three families had LFS and 7 families had LFLS. Two of the 3 families with LFS and 1 in 7 families with LFLS carried mutations. In addition, out of 21 patients with a family history of breast cancer without LFS or LFLS, none carried mutations in TP53. In this selected population, about 1% of families with hereditary breast cancer may carry mutations in TP53. Another study suggests that that one in 5000 women with breast cancer harbors a TP53 mutation [32]. Hence, in the absence of genomic rearrangements within the BRCA1 and BRCA2 genes, TP53 mutations screening should be considered in women with a strong family history of breast cancer and features of LFS or LFLS.

Table 1.

Criteria for Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like syndrome (LFLS)

Li-Fraumeni Syndrome (LFS) Sarcoma <45 yo with 1st degree relative < 45yo with cancer and 1st or 2nd degree relative < 45yo with any cancer [34].
Li-Fraumeni-like syndrome (LFLS) Sarcoma, brain tumor or adrenocortical carcinoma < 45yo or childhood leukemia and 1st or 2nd degree relative with LFS tumor and 1st or 2nd degree relative < 60yo with cancer [6].
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PTEN

  • PTEN (phosphatase and tensin homolog) is a tumor suppressor gene that inhibits cell growth during the G1 phase of cell cycle by activating the cyclin-dependant kinase inhibitor p27(KIP1) [33]. Mutations in PTEN are rare, but are associated with a high penetrance syndrome termed Cowden disease (CD). Individuals with Cowden syndrome have a high risk for developing breast cancer as well as hamartomas and benign tumors in the skin, thyroid, breast, endometrium, and brain. At least three different mutations in PTEN have been found in families with CD and early onset breast cancer [51].

Lifestyle factors that affect breast cancer risk

  • Many factors influence the penetrance of tumor susceptibility genes, such as environmental factors, carcinogens, hormonal factors, and lifestyle factors. Hormonal factors that influence breast cancer risk include age at menarche, pregnancy, breast-feeding, and contraceptive use. However, these environmental factors may not be strong enough to change the penetrance of the BRCA genes. For example, an early age of onset of menstruation increases a woman’s risk of breast cancer [24]. A recent study, though, involving 3947 women showed no correlation between carrying either BRCA1 or BRCA2 mutations with age of menarche (P = 0.97). However, a matched case-control study with 1311 pairs, showed that for each year that menarche was delayed after age 11 in BRCA1 carriers, there is a 15% decreased risk of breast cancer (PTrend = 0.0002). For women who experienced menarche at 15 years or older, there is a 54% reduced risk of breast cancer compared to those who experienced it before age 11.

  • Pregnancy is associated with a protective effect against the early onset of breast cancer in the general population. Although mutations in BRCA1 or BRCA2 are associated with a decreased age of breast cancer onset, the protective effects of pregnancy were the same as in wild-type patients. In the general population, childbirth reduces the risk of breast cancer by 23% (P = 0.009), and among women negative for either of BRCA-gene mutation, the risk is similarly decreased. BRCA-gene mutation carriers seem to have a 29% decreased risk of breast cancer after childbirth, with a similar risk reduction to women who do not have a mutation in either gene (P = 0.26) [26]. In addition, for women over the age of 40, each additional birth leads to a 14% reduction in the risk for breast cancer in the general population (95% CI = 6–22% Ptrend = 0.008). This trend is seen regardless of BRCA-gene mutation status [3].

  • It has also been shown that a healthier adolescent lifestyle, measured by adolescent weight within normal limits and physical activity, protects against the risk of early onset of breast cancer. Physical activity among teenagers led to a decrease in early onset breast cancer (P = 0.025 in all study participants, and P = 0.034 for women with mutations in the BRCA genes) [26]. A study on 11,889 females with breast cancer from Taiwan found that both an increased BMI and hip circumference were associated with an increased risk for breast cancer. Compared to a BMI less than 21.6 kg/m2, having a BMI over 26.2 kg/m2 resulted in a relative risk of 1.9 (95% CI = 1.0–3.4), and compared to a hip circumference of less than 90 cm, one over 100 cm resulted in a RR = 2.9 (95% CI = 1.1–6.7; PTrend = 0.0485) [54]. For BRCA carriers, the OR associated with a 35 pounds weight gain after the age of 18 was found to be 4.64 (95% CI = 1.52–14.12; PTrend = 0.011) compared to those who gained less than 12 lbs.

Genetic testing

  • Genetic testing is carried out for families with a high risk of breast and ovarian cancer (Table 2). The criteria for “high risk” is outlined in the National Comprehensive Cancer Network’s (NCCN) Clinical Practice Guidelines in Oncology [1].

  • Genetic screening for breast cancer consists of screening for mutations in BRCA1 and BRCA2 (Table 3). If the family history is suggestive of either Cowden syndrome of Li-Fraumeni syndrome testing for mutations in PTEN or TP53 may be indicated.

Table 2.

Criteria for genetic testing for BRCA gene mutations

• Early age (< 40) at the onset of breast cancer with or without a family history of breast cancer
• 2 primary breast cancers or breast and ovarian cancer in a single patient or 2 primary breast or breast and ovarian cancers in close relatives from the same side of the family
• a clustering of breast cancer with male breast cancer, thyroid cancer, sarcoma, adrenocorticoid cancer, endometrial cancer, pancreatic cancer, brain tumors, dermatologic manifestations, or leukemia/lymphoma on the same side of the family
• A member of the family with known mutations in breast cancer susceptibility genes
• Population at risk (such as the Ashkenazi Jewish population)
• Any male breast cancer
• Personal history of ovarian cancer
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Table 3.

Results of genetic screening for BRCA1/2 mutations

Result Interpretation
Positive for deleterious mutation Individual has high risk of breast and ovarian cancer
Negative for a mutation Result interpreted with caution especially in the setting of a strong family history
Mutation of unknown significance Mutation has not been definitively shown to be deleterious either because it is rare or because it may not completely track with the family history of the individual
Mutation favoring benign polymorphism Although not certain these mutations seem to not be associated with a high risk for breast and ovarian cancer
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Patient management

  • For women with a family history of breast cancer, genetic testing may be a useful tool to guide management options. If a woman has a family history of breast cancer and carries a BRCA1 or BRCA2 mutation, medical and surgical interventions have been shown to reduce the risk of cancer. The most effective options include prophylactic bilateral mastectomy and prophylactic salpingo-oophorectomy. However, these procedures are highly invasive and there are other nonsurgical risk-reducing interventions. Increased surveillance has also been shown to increase early detection.

Prophylactic mastectomy

  • Prophylactic mastectomy (PM) is the most effective strategy for reducing the risk of breast cancer in high risk individuals. A study by Hartmann et al in 1999 was the first to demonstrate a 90% reduction in breast cancer in high risk families after bilateral PM, regardless of BRCA1 or BRCA2 status. Subsequent studies have confirmed this reduction in breast cancer risk [11].

Prophylactic salpingo-oophorectomy

  • BRCA1 and BRCA2 mutation carriers have a decreased risk of both ovarian and breast cancer after prophylactic salpingo-oophorectomy (PSO). For ovarian cancer, PSO is the best intervention, as screening is virtually ineffective [11]. PSO reduces the risk of ovarian cancer by 85–96% [11,15,23,45]. However, when PSO is performed in premenopausal women, it is also associated with a significant decrease in the risk of breast cancer. In the same studies there was a 53–68% reduced risk of breast cancer after PSO. Eisen et al have shown that a greater risk reduction for breast cancer is achieved when prophylactic surgery is performed prior to age 40 (OR 0.36; 95% CI 0.20–0.64) compared to after age 40 years (OR = 0.53; 95% CI = 0.3–0.91). This risk reduction was observed only in BRCA1 mutation carriers, probably due to the smaller numbers of BRCA2 mutation carriers. When PSO is done at an early age, the protective effects are seen for a minimum of 15 years [13]. For BRCA1/2 mutation carriers, the 10 year breast cancer incidence for a 40-year old woman decreases from 32% to 11% after PSO; at age 50 it decreases from 28% to 19%, and at age 60 the 10 year risk decreases from 25 to 14% [28].

  • One concern for many women who consider bilateral PSO as a form of prevention is the onset of premature surgical menopause, which may affect their quality of life. Hormone replacement therapy (HRT) alleviates these symptoms, however when combined with estrogen-progesterone use, it is also associated with an increased risk of breast cancer [46]. Rebbeck et al recently determined that short term HRT usage does not alter breast cancer risk in patients who have undergone bilateral PSO (HR = 0.37; 95% CI = 0.14–0.96) compared to the overall risk of breast cancer after bilateral PSO (HR = 0.40; 95% CI = 0.18–0.92). The impact of long term usage of HRT on the risk of breast cancer for women having undergone bilateral PSO is yet to be studied [44].

Surveillance

  • Patients at high risk for breast cancer due to a strong family history or predisposed genetic background should get an annual mammography and breast MRI, as well as semiannual clinical breast exams (CBE). For identifying invasive breast cancer, MRI has a higher sensitivity than mammography and CBE (79.5%, 33.3%, and 17.9%, respectively). The specificities for these methods are 89.8%, 95%, and 98.1%, respectively. The sensitivity rates for any type of tumor detection are: 17.8% for CBE, 40% for mammography, and 71.1% for MRI. The use of MRI screening has been shown to detect invasive tumors at an earlier stage (less than 10 mm) compared to individuals not receiving MRI for screening [30].

  • Kriege and colleagues found that the sensitivity of MRI screening is much higher than that of mammography in patients with glandular breast tissue (low breast density) (93.3% vs. 46.7% P = 0.04). Although the difference in sensitivity is not as high in women with dense breast tissue (58.6% MRI vs. 37.9% mammography; P = 0.3), MRI still has a higher overall sensitivity compared to mammography[29].

  • Because BRCA1 and BRCA2 encode proteins that play a role in DNA repair after ionizing radiation, there has been some concern that individuals who carry mutations in either one of these genes would have an increased risk for breast cancer with mammographic screenings [17]. Narod and colleagues conducted the first case control study using 1600 matched cases and controls looking at mammography screening and risk of breast cancer in BRCA1 and BRCA2 mutation carriers. They found no association between ever having a mammography and risk of breast cancer for BRCA1 or BRCA2 mutation carriers (OR 1.04; 95% CI = 0.84–1.29 vs OR 1.06; 95% CI = 0.67–1.66, respectively) [40]. However, for BRCA-gene mutation carriers, the risk for breast cancer before the age of 40 is significantly increased after exposures to chest x-rays that were taken before the age of 20 (HR = 2.61; P < 0.01). This risk is also significant for women born after 1949 (HR = 4.64; P < 0.001) [2]. Based on these limited studies our recommendation is to avoid non-necessary ionizing radiation in BRCA-gene mutation carriers, especially among women 20 years old or younger.

Chemoprevention

  • Besides risk-reducing surgeries there are other strategies that may have an impact on breast cancer risk. Medications such as tamoxifen have been used for years in the treatment of breast cancer. Several studies have suggested a significant benefit in reducing the risk of breast cancer in high risk individuals. The NSABP P-1 trial showed that in 13,388 women with a predicted breast cancer risk of over 1.66, use of tamoxifen for 5 years offered a reduction in breast cancer by 43% after a median follow-up of 7 years [16]. In that trial eight women with a BRCA1 mutation developed breast cancer. Of those, five were in the tamoxifen arm whereas three were in the placebo arm [25] and six of the eight women developed an estrogen receptor (ER) negative breast cancer. In the same study population, 11 women with a BRCA2 mutation developed breast cancer. Of those, three were in the tamoxifen arm and eight in the placebo arm conferring a 62% reduction in breast cancer risk. Furthermore, six of the breast cancers were found to be ER positive. The number of BRCA-gene mutation carriers in this trial is small and precludes any definite conclusion with respect to the benefit of tamoxifen in BRCA-gene mutation carriers. It does, however, suggest that BRCA2-mutation carriers may derive a benefit from tamoxifen chemoprevention as the majority of breast cancers among BRCA2 carriers are ER positive. In another chemo-prevention trial, the Royal Marsden trial, there were only four identified BRCA-gene mutation positive individuals and therefore a potential benefit from tamoxifen could not be assessed [27]. In another study of 491 women with BRCA-gene mutation positive breast cancer, use of tamoxifen significantly decreased the risk of contralateral breast cancer (HR, 0.59; 95% CI, 0.35–1.01) [38]. Other studies have also confirmed the beneficial effect of tamoxifen on breast cancer prevention in BRCA1-and BRCA2-mutation carriers [20,39].

  • In another study Markov modeling of outcomes was performed in a simulated cohort of 30-year old women who tested positive for BRCA1/2 mutations [19]. Investigators found that the addition of tamoxifen as chemoprevention prolonged survival by 1.8 years over what surveillance would offer.

  • Therefore, although the data on tamoxifen chemoprevention in BRCA-gene mutation carriers is not overwhelming there seems to be a benefit in reducing the risk of breast cancer. The potential benefit from other chemopreventive strategies, such as raloxifene and aromatase inhibitors, will probably be limited since these agents are only being used in postmenopausal women. However, future trials will address these issues.

Low penetrance genes

  • Cancer due to BRCA1 or BRCA2 mutations account for only about 3–8% of all breast cancer cases. Other genes have been identified as breast cancer susceptibility genes, which may account for a proportion of the remainder of heritable breast cancer cases. These genes include BRIP1, CHEK2*1100delC, and TGFBR1*6A. They are considered low penetrance breast cancer susceptibility genes because only a small fraction of individuals who carry these genes will ultimately develop cancer.

CHEK2

  • CHEK2 is a cell cycle checkpoint protein that mediates mitotic block in the presence of ionizing radiation-induced DNA damage. Thus inactivating mutations in CHEK2 would promote cancerous growth in the presence of DNA damage. The CHEK2*1100delC mutation abolishes kinase activity of the protein, thereby blocking signaling by CHEK2.

  • The CHEK2*1100delC variant is present in 1.1% of the population. In contrast, 5.1% of breast cancer patients who are wildtype for the BRCA genes carry this mutation. Women carriers of CHEK2*1100delC have a two-fold increased risk for breast cancer compared to the normal population [36].

  • The role of CHEK2*1100delC in male breast cancer is controversial. Meijers-Heijboer’s study in 2002, which included patients from the UK, North America, the Netherlands, and Germany, found the CHEK2*1100delC mutation in 13.5% of patients from families with male breast cancer [36]. The risk for breast cancer in men who carry CHEK2*1100delC is increased ten-fold, and 9% of male breast cancer cases are estimated to arise from CHEK2*1100delC. Other studies have not been able to link CHEK2*1100delC to male breast cancer cases [50,53].

BRIP1

  • BRIP1 (also known as BACH1) encodes a helicase that functionally interacts with the BRCA1 gene to contribute to DNA repair [8]. A recent study found that BRIP1 was mutated in 9 out of 1,212 individuals (0.74%) with breast cancer who had a family history of breast cancer. Within these 9 people, there were five different types of truncating mutations. These patients carried wildtype BRCA genes. In the control group, which consisted of 2,081 people chosen from a 1958 Birth Cohort Collection in Great Britain, only 2 people (0.1%) had truncating mutations (P = 0.0030), conferring an estimated relative risk of breast cancer associated with BRIP1 truncated mutations to be 2.0 (95% CI = 1.2–3.2; P = 0.012) [47].

TGF-b pathway variants

  • Transforming growth factor beta (TGF-b) has a dual role in cancer development. In normal mammary epithelial and breast carcinoma cells, TGF-b inhibits cell proliferation, however, as the tumor progresses TGF-b enhances invasion and metastasis [52]. Thus, loss-of-function mutations in the TGF-b signaling pathway in the early stages of oncogenesis would contribute to tumor growth due to the lack of growth inhibitory signals. Gain-of-function mutations benefit the late steps in tumor metastasis.

  • TGFBR1*6A is a common variant of TGFBR1, which received its name from the three alanine deletion from a nine alanine tract in the receptor’s signal sequence. TGFBR1*6A has been shown to mediate TGF-b growth inhibitory signals less efficiently in reporter assays and growth inhibition assays in mink lung epithelial cells [9,43]. Importantly, TGFBR1*6A has been shown to switch TGF-b growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells, which strongly suggests that TGFBR1*6A provide a selective growth advantage to cancer cells in the TGF-b-rich tumor microenvironment [42]. A recent meta-analysis of 17 case-control studies that included 13,113 individuals has shown that TGFBR1*6A carriers have a 22% increased risk of cancer. With respect to breast cancer this study showed that TGFBR1*6A homozygotes have almost a three-fold increased risk as compared with non-carriers (OR 2.69, 95% CI 1.54–4.68) [57]. Given the high TGFBR1*6A carrier frequency in the general population (14.1%), the population attributable breast cancer risk is 4.9% (2.7–7.2%) (Table 4).

  • Several polymorphisms have been found in the TGFB1 gene. Two specific polymorphisms modulate the level of circulating TGF-b: Arg25Pro (resulting from a C to T substitution at position 509) and Leu10Pro (resulting from a T to C substitution at position 29) [18,55]. The Leu10Pro variant results in increased levels of TGFB1 secretion [12,55]. In a cohort study of 3,075 White American women over the age of 65 the authors found that the risk of breast cancer decreased 64% in TGFB1*CC carriers compared to subjects that were TGFB1*CT or TGFB1*TT [58]. However, two studies have shown that there is no correlation between woman carrying the C allele and the risk of breast cancer [21,31]. A recent study using patients from the Shanghai Cancer Registry, could not correlate breast cancer risk with TGFB1*CC or CT [48]. Thus, the association between this SNP and breast cancer remains to be clarified.

  • We have recently investigated the combined genetic assessment of TGFBR1*6A and TGFB1 T29C. Patients and controls were divided into three groups based on combination of these two functionally-relevant variants and categorized into high, intermediate, and low constitutive TGF-b signalers. Low signalers had a 70% increased breast cancer risk as compared with high signalers (OR 1.69, 95% CI 1.08–2.66), which is consistent with the known role of TGF-β in animal models of breast cancer. Importantly, this approach was able to predict breast cancer risk in 30% of the population. If ongoing studies confirm this association, TGF-β pathway analysis may become a useful clinical tool to predict breast cancer risk in the near future [22].

  • The field of breast cancer susceptibility genes is rapidly evolving. Integration of novel breast cancer susceptibility genes is likely to provide effective new means of breast cancer prevention within the next few years.

Table 4.

Clinical relevance of low-penetrance breast cancer susceptibility genes

Population frequency Hazard ratio (95% C.I) Population attributable risk (PAR)
TGFBR1*6A 0.5% homozygotes O.R. 2.69 (1.54–4.68) 4.9% (2.7%–7.2%) of all breast cancers
14.1% heterozygotes O.R. 1.23 (1.06–1.43)
CHEK2 0.5% heterozgotes O.R. 1.5 (1.2–1.8) Less than 0.5% of all breast cancers
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J Clin Onc 57, 23:7743-7743; Am J Hum Genet 2004, 74:1175-82; Clin Cancer Res 2006, 12:4832-4835.

Reference and Recommended Reading

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