ATM Gene mutation
Having a mutation or fault in the ataxia-telangiectasia mutated (ATM) gene is associated with an increased risk of breast cancer.
ATM is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer. About 1% of men and women carry a fault in ATM*.
Women who have an ATM gene fault have about 1.7 times higher risk of breast cancer compared to women in the general population. There is one specific gene fault associated with a somewhat higher risk of breast cancer.
Most women who carry an ATM gene fault will not develop breast cancer.
* If two mutation carriers have a child, there is a 1 in 4 chance that the child will have a very rare, serious condition known as ataxia-telangiectasia (AT). AT is a rare genetic disorder that affects the nervous system and other body systems. It is caused by having two ATM gene faults, one from each parent. Most children with AT are diagnosed between the ages of 1 to 4 years. Carriers of a single mutation in the ATM gene do not get ataxia-telangiectasia.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that having a mutation or fault in the ATM gene is associated with an increased the risk of breast cancer.
Women who are heterozygous carriers of an ATM mutation are estimated to have 1.74 (95% CI 1.46–2.07) times the risk of breast cancer compared to women without an ATM mutation.[1] The risk of breast cancer is higher if a woman carrying the ATM gene mutation has relatives with ataxia-telangiectasia (RR 3.0, 95% CI 2.1–4.5) and the risk is also higher among younger women than older women.[2]
Mechanisms
The ATM gene codes for a protein that has a key role in DNA repair. Mutations in the gene can allow DNA damage to accumulate, which can lead to formation of cancerous tumours. Approximately 1% of the population are heterozygous carriers of an ATM gene mutation.
Homozygous ATM gene mutations are associated with ataxia-telangiectasia (A-T), a rare autosomal recessive genetic disease occurring in 1 in 40,000 to 1 in 100,000 people, which begins in childhood and affects the nervous system. A-T increases the risk of several cancers, including leukaemia and lymphoma.
Evidence
Recent studies include a large case-control study using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk. This study found that heterozygous carriers of an ATM gene mutation had a risk of breast cancer that was 1.74 times (95% confidence interval [CI] 1.46–2.07) higher than in women without the mutation.1 Several other case-control studies and meta-analyses of cohort studies among A-T family members have also found that breast cancer risk is increased in women who are heterozygous carriers of an ATM mutation.
Two meta-analyses of cohort studies[2,3] have shown that the increased risk of breast cancer is higher among women with familial A-T who are heterozygous carriers of an ATM mutation (relative risk [RR] 3.0, 95% CI 2.1–4.5 and RR 2.8, 95% CI 2.2–3.7; respectively). The increased breast cancer risk was shown to be substantially higher for heterozygous younger women (aged less than 45–55 years) in A-T families than for women aged older than 55 years in A-T families (RR 7.0, 95% CI 4.1–11.9 versus RR 2.1, 95% CI 1.2–3.6).[2]
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CHEK2 Gene mutation
Having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.
CHEK2 is considered to be a rare, moderate-risk gene, meaning that a fault in this gene is associated with a moderately increased risk of breast cancer.
Women who have a CHEK2 gene fault have about 2 times the risk of breast cancer compared to women in the general population.
Few women are carriers of a CHEK2 gene fault and most women who carry a CHEK2 gene fault will not develop breast cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.
Women who are carriers of a CHEK2 mutation are estimated to have 1.99 (95% CI 1.70–2.33) times the risk of breast cancer compared to women without a CHEK2 mutation.[1]
The estimated risk associated with a CHEK2 gene mutation depends on the specific type of mutation, with the increased risk for the most studied variant, CHEK 1100delC mutation, estimated to be between 2.31 (95% CI 1.88–2.85)[4] and 3.10 (95% CI 2.59–3.71)[5] times the risk of women without this mutation.
Mechanisms
The CHEK2 gene codes for the checkpoint kinase 2 (CHK2) protein. This protein is a tumour suppressor protein, which prevents cells from growing and dividing too rapidly or in an uncontrolled way.[6] Mutations in the CHEK2 gene can allow cells with damaged DNA to continue dividing, leading to the development of cancer.
The CHEK 1100delC mutation, which has been most extensively studied, occurs mainly in individuals of northern and eastern European descent, and has a frequency of approximately 1% in these populations.[7]
Evidence
A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the CHEK2 gene were associated with increased breast cancer risk.[1] The odds ratio (OR) was 1.99 (95% confidence interval [CI] 1.70–2.33), adjusted for family history of breast cancer.
Another large case-control study, using results of germline multigene panel tests found that CHEK2 mutations were associated with an increased risk of breast cancer in women of European ancestry (OR 2.26, 95% CI 1.89–2.72).[4]
A meta-analysis found an approximately three times increased risk of breast cancer associated with CHEK2 mutations among high-risk women.[8] A similarly increased risk associated with CHEK2 mutations was also found in a UK population-based case-control study, with a stronger association found for oestrogen-receptor-positive (ER+) breast cancer than for oestrogen-receptor-negative (ER–) breast cancer.[9]
Four meta-analyses[3,5,10-13] and a large case-control study2 have indicated that the CHEK 1100delC mutation is associated with increased breast cancer risk, with risk estimates ranging from 2.31 (95% CI 1.88–2.85)[4] to 3.10 (95% CI 2.59–3.71)[5].
An increased risk of breast cancer has also been found with several other, but not all, specific CHEK2 gene mutations.[5,12,13]
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PALB2 Gene mutation
Having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.
PALB2 is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer.
Women who have a PALB2 gene fault have at least 3 times the risk of breast cancer compared to women in the general population. PALB2 gene mutations may also be linked to an increased risk of pancreatic cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.
Women who have a PALB2 mutation are estimated to have 3.39 (95% CI 2.79–4.12)[1] times the risk of breast cancer compared to women without a PALB2 mutation.[1] Higher risks of breast cancer associated with a PALB2 mutation have been estimated in other studies conducted among women with histories suggestive of hereditary breast cancer predisposition.
Mechanisms
The PALB2 gene codes for the ‘Partner and localizer of BRCA2’ (PALB2) protein. The PALB2 protein interacts with the BRCA1 and BRCA2 proteins. This complex plays a key role in DNA repair. Mutations in the PALB2 gene disrupt this repair pathway, and can thereby increase the risk of cancer.[14]
Approximately 0.2% of the population are estimated to carry a mutation in the PALB2 gene.[15]
Evidence
A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the PALB2 gene were associated with an increased risk of breast cancer, with an odds ratio [OR] of 3.39 (95% confidence interval [CI] 2.79–4.12), adjusted for family history of cancer.[1]
A population-based case-control study of 18,575 women in the United Kingdom indicated an odds ratio of 4.69 (95% CI 2.27–9.68) between women with PALB2 mutations and increased breast cancer risk.[9]
Risk estimates are higher among studies which have included women at higher risk of breast cancer due to a family history of cancer. For example, a large case-control study using results of multigene panel tests among women with clinical histories suggestive of hereditary breast cancer predisposition, found that PALB2 mutations were associated with 6.25 times increased risk of breast cancer (95% CI 4.82–8.14).[4]
In a meta-analysis[3] of three studies, including a study among women with a family history of breast cancer and a germline PALB2 mutation,[16] the estimated relative risk of breast cancer associated with PALB2 gene mutations was 5.3 (90% CI 3.0–9.4). A similarly higher estimate of breast cancer risk associated with mutations in the PALB2 gene has also been found in another meta-analysis of case-control studies among high-risk groups of women.[8]
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References
[1] Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
[2] van Os NJ, Roeleveld N, Weemaes CM, et al. (2016). Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clinical Genetics 90:105–117.
[3] Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
[4] Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
[5] Zhang B, Beeghly-Fadiel A, Long J, et al. (2011). Genetic variants associated with breast cancer risk: comprehensive field synopsis, meta-analysis, and epidemiologic evidence. Lancet Oncology 21(5):477–488.
[6] United States National Library of Medicine (2018). Genetics Home Reference: CHEK2 gene, https://ghr.nlm.nih.gov/gene/CHEK2.
[7] Meijers-Heijboer, van den Ouweland A, Klijn J, et al. (2002). Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genetics 31(1):55–59.
[8] Aloraifi F, McCartan D, McDevitt T, et al. (2015). Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. Cancer Genetics 208:455–463.
[9] Decker B, Allen J, Luccarini C, et al. (2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of Medical Genetics 54:732–741.
[10] Yang Y, Zhang F, Wang Y et al. (2012). CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls. Asian Pacific Journal of Cancer Prevention 13:3501–3505.
[11] Weischer M, Bojesen SE, Ellervik C, et al. (2008). CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. Journal of Clinical Oncology 26(4):542–548.
[12] Southey MC, Goldgar DE, Wingvist R, et al. (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics 53:800–811.
[13] Liu C, Wang Y, Wang QS et al. (2012). The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention 13:1355–1360.
[14] Cybulski C, Kluźniak W, Huzarshki T, et al. (2015). Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncology 16:638–644.
[15] United States National Library of Medicine (2018). Genetics Home Reference: PALB2 gene, https://ghr.nlm.nih.gov/gene/PALB2.
[16] Antoniou AC, Casadei S, Heikkinen T, et al. (2014). Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine 371(6):497–506.
