Breast cancer

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Wikipedia provides a good introduction to breast cancer

Advice from the National Cancer Institute


In general, the mutations that are recognized to increase breast cancer risk within families are quite rare; these include mutations in the ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS1, PMS2, PTEN, RAD50, RAD51C, STK11 and TP53 genes. All together, these rare mutations probably account for a small (2 to 5%) percentage of breast cancer cases. Therefore, the most effective manner to assess familial breast cancer risk is not via SNP testing, but rather through identifying (if possible) the specific causative mutations within one's family and then testing relatives for those variations.

A free risk "breast cancer risk evaluator" calculator is available online courtesy of the US National Cancer Institute. A more detailed, though not peer-reviewed, version of this calculator is also available.

The Ohio State University Medical Centeral also offers a cancer and coronary heart disease risk tool Family HealthLink published at [PMID 14757853].

2009 review: Breast cancer susceptibility: current knowledge and implications for genetic counselling [PMID 19092773]

If using family history to estimate breast cancer risk is not possible, one alternative is to simply tally up the number of breast cancer risk alleles, in order to estimate an overall risk score. At least one study [PMID 17341484] has reported that overall risk can be (somewhat) estimated from looking at risk alleles that by themselves would each present too small a risk to look at independently. The SNPs considered to have risk alleles for breast cancer were primarily from the genes already mentioned, and included:

As for how to calculate the (estimated!) risk, this report [PMID 17341484] provides two different algorithms. The first is to simply count the number of risk alleles for these 25 SNPs, i.e. the # of rarer alleles for each SNP. (A homozygote for a rare allele ups the count by 2.) The odds ratio associated with increasing numbers of risk alleles is reported as follows:

0: 1.00 (by definition)
1: 1.46 (CI: 0.89 - 2.40)
2: 1.39 (CI: 0.86 - 2.25)
3: 1.75 (CI: 1.09 - 2.80)
4: 1.56 (CI: 0.95 - 2.55)
5: 1.31 (CI: 0.76 - 2.24)
6: 1.84 (CI: 1.04 - 3.26)
7: 2.10 (CI: 1.06 - 4.16)
8: 4.02 (CI: 1.56 - 10.38)
9 or more: 8.04 (CI: 1.89 - 34.26)

The second way to calculate overall risk for breast cancer reported by these authors involved counting the total of only the alleles that had relative frequencies (in their control population) of less than 10%. The simplest way to do this is to count the alleles for the same 25 SNPs presented above, but ignoring the 4 that have minor allele frequencies of over 10%, which are SNPs rs16942, rs1799966, rs144848, and rs1042522. Relative risk reported for this total count was:

0: 1.00 (by definition)
1: 1.24 (CI: 0.99 - 1.54)
2: 1.51 (CI: 1.10 - 2.09)
3: 2.90 (CI: 1.69 - 4.97)

It should be noted that having several minor (risk) alleles is quite common; in fact, 97% of women who did not have breast cancer had 0, 1, or 2 minor risk alleles, and even 1.4% of these women had 3 risk alleles (vs. 4% of women with breast cancer who had 3 risk alleles, for example).

Furthermore, the use of SNPs to predict breast cancer risk has been found to be less accurate than traditional methods, according to a 2008 study [PMID 18612136], and even when performed in combination with traditional methods, of little additive value. On the other hand, in the absence of family information and physical data, genetic data may be easier to collect and analyse.

Certain individuals may also find 23andMe's report template pdf to be of interest.


Some SNPs have been reported to influence breast cancer progression, though not the odds of having it; these include:


As for the good news, some SNPs are associated with lower risk for breast cancer; these include:

Other genes that may affect the risk of breast cancer include:

Several SNPs have been linked to poorer survival odds in patients diagnosed with breast cancer, irrespective of whether they affect the odds of having it:


The Genes-to-Systems Breast Cancer Database lists breast cancer genes correlated with the cell cycle process.


Aside from risk of disease, there are SNPs that play a role in how patients respond to drugs used to treat breast cancer.

  • rs351855 is associated with a particular form of breast cancer and the efficacy of Herceptin.
  • [PMID 17115111] CYP2D6 metabolism is an independent predictor of Breast cancer outcome in post-menopausal women receiving Tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.
  • CYP2D6 poor metabolizers may not benefit from the use of tamoxifen as significantly as others for the treatment of breast cancer, prompting the recommended relabeling of this drug


The following SNPs have also been linked to breast cancer

rsnum gene
rs2056116
rs3218005
rs2854344
rs3817198 LSP1
rs2268578 LUM
rs889312 MAP3K1
rs3803662 TNRC9
rs2981582 FGFR2
rs4151620
rs12255372 TCF7L2
rs1045485 CASP8
rs351855 FGFR4
rs361525 TNF
rs1801270 CASP8
rs203462 AKAP10
rs1219648 FGFR2
rs1042638 TPD52
rs997669 CCNE1
rs3176336 CDKN1A
rs34330 CDKN1B
rs3731239 CDKN2A
ATM
BRCA2
BRIP1
CHEK2
CYP2D6
HMMR


The Icelandic company deCODE launched a $1625 BreastCancer™ test in October 2008 that determines the genotypes for 7 known SNPs that have been linked to female breast cancer. Note that this test is not a direct-to-consumer test; it is only available through a licensed physician. The 7 SNPs assayed are:

From deCode: "The deCODE BreastCancer™ test reports the subject’s measured genetic risk of breast cancer relative to the average population and the lifetime risk of being diagnosed with breast cancer. The relative risk of breast cancer determined by the test can vary from 0.45 for subjects who are homozygous (2 copies) for the protective variants at all 7 markers, to 3.77 for subjects who are homozygous for risk variants at all markers. About 42% of the female population has genotype combinations of the tested markers that confer an increased relative risk (>1) of breast cancer. Ten percent of women in the general population have genotypes that confer more than a 40% increase in the relative risk of breast cancer, about 5% would be considered high risk with a 1.66-fold or greater risk (corresponding to a lifetime risk of 20% or greater), and approximately 1% of women have an average 3-fold risk (37% lifetime risk)."


omim summarizes the latest research


[PMID 16768547] Breast Cancer Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

The relative risk of breast cancer associated with PALB2 mutations was estimated to be 2.3 ( two-fold ). This is similar to the increase in risk seen with the CHEK2, ATM and BRIP1 genes – all reported by the same research group since 2002. PALB2 is the first low-risk gene protein product found that interacts with BRCA2 – all of the other low-risk genes, CHEK2, ATM and BRIP1, are linked to BRCA1. Together, these genes are thought to account for around two per cent of all breast cancer cases. [1]


This article pools the data from several different studies to identify 5 snps which consistently demonstrate relevance to breast cancer


breast cancer


The mannose-binding lectin (MBL2) haplotype and breast cancer: an association study in African American and Caucasian women.

This study presents preliminary evidence that common genetic variants in the 3' UTR of MBL2 might influence the risk for breast cancer in African American women, probably in interaction with the 5' secretor haplotypes that are associated with high concentrations of mannose binding lectin. [PMID 17071626]


Breast Cancer Gene Mutations More Common Than Thought provides a nice summary of this research paper


In contrast to the discussion of the SNPs underlying familial cases of breast cancer, this paper discusses genetic risk factors underlying sporadic cases [PMID 16835078].


[PMID 17908970] The AA Genotype of the Regulatory BCL2 Promoter Polymorphism ( 938C>A) Is Associated with a Favorable Outcome in Lymph Node Negative Invasive [breast cancer] Patients. Bachmann HS, Otterbach F, Callies R, Nückel H, Bau M, Schmid KW, Siffert W, Kimmig R.

Authors' Affiliations: Institutes of Pharmacogenetics and Pathology and Neuropathology.

PURPOSE: Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (-938C>A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities. EXPERIMENTAL DESIGN: Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (-938C>A) genotypes were correlated with the patients' survival. RESULTS: Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node-negative breast cancer patients, whereas no genotype effect could be observed in lymph node-positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (-938CC) genotype as an independent prognostic factor for cancer-related death in lymph node-negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node-positive but not of lymph node-negative breast cancer patients. In lymph node-negative cases, the (-938C>A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2-expressing carcinomas (P = 0.006). CONCLUSIONS: These results suggest the (-938C>A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node-negative breast cancer.