What is an ATM (Ataxia-Telangiectasia Mutated) mutation?

ATM Mutation: A Critical DNA Repair Gene with Significant Cancer Implications

An ATM (Ataxia-Telangiectasia Mutated) mutation is a genetic alteration in the ATM gene that encodes a protein kinase critical for DNA damage response, cell cycle checkpoint regulation, DNA repair, and apoptosis regulation, which when mutated can lead to increased cancer risk, particularly breast, pancreatic, and prostate cancers. 1

ATM Gene Function and Structure

The ATM gene is located on chromosome 11q22-23 and encodes a protein belonging to the phosphatidylinositol-3 kinase (PI3K) family. This protein functions as:

• A cell cycle checkpoint kinase that regulates multiple proteins including tumor suppressors p53, BRCA1, CHEK2, and NBS1 1
• A central regulator in DNA damage response, particularly in response to double-strand DNA breaks 2
• A critical component in maintaining genomic stability 1

The ATM protein contains a critical PI3K domain at its carboxy terminus that is essential for its function in DNA damage response 3.

Types of ATM Mutations

ATM mutations can be categorized as:

1. Biallelic mutations - When both copies of the ATM gene are mutated, causing Ataxia-Telangiectasia (A-T)
2. Heterozygous mutations - When one copy of the ATM gene is mutated (carrier state)
3. Specific missense variants - Some variants like NM_000051.4:c.7271T>G p.(Val2424Gly) confer higher cancer risks than typical truncating variants 1

Clinical Manifestations

Biallelic ATM Mutations (Ataxia-Telangiectasia)

When both copies of the ATM gene are mutated, it causes Ataxia-Telangiectasia (A-T), characterized by:

• Progressive cerebellar ataxia (typically appearing between 1-4 years of age) 1, 4
• Oculomotor apraxia and choreoathetosis 1
• Conjunctival telangiectasias 1
• Immunodeficiency with frequent infections 4
• Increased sensitivity to ionizing radiation 1
• High risk of malignancy (up to 40% of patients), typically non-Hodgkin lymphoma and acute lymphoid leukemia 1
• Most children become wheelchair-bound by their teen years 1

Heterozygous ATM Mutations (Carriers)

Individuals with one mutated ATM gene (carriers) have:

• No symptoms of Ataxia-Telangiectasia 5
• Increased risk of developing certain cancers 1, 5
• Reduced life expectancy due to mortality from cancer and ischemic heart diseases (RR 1.7,95% CI 1.2-2.4) 5

Cancer Risks Associated with ATM Mutations

Breast Cancer

• Women with heterozygous ATM mutations have approximately 2-3 fold increased risk of breast cancer (RR 2.37,95% CI 1.5-3.8) 1, 5
• Higher risks (3-5 fold) are observed in women younger than 50-55 years 1
• Specific variants like c.7271T>G can confer much higher risks (up to 52-60% by age 70-80) 1

Pancreatic Cancer

• ATM mutations are found in approximately 2.1% of pancreatic adenocarcinoma patients 1
• Patients with ATM mutations tend to be younger at diagnosis and have longer overall survival compared to those without such mutations 1

Prostate Cancer

• ATM mutations are found in approximately 2% of metastatic prostate cancer patients 1
• Associated with earlier age of metastatic disease and death 1
• Meta-analysis showed pooled odds ratio of 1.93 (95% CI, 1.17-3.20) for prostate cancer progression 1

Other Cancers

• Increased risk of digestive tract cancers 5
• Possible associations with colorectal cancer, ovarian cancer, and melanoma, though larger studies are needed for confirmation 1
• Some evidence of association with gastric cancer 6

Surveillance Recommendations for ATM Mutation Carriers

Breast Cancer Surveillance

• Female carriers aged 40-50 years should be offered intensified surveillance programs for breast cancer 5
• Female carriers of the specific c.7271T>G mutation should begin surveillance from age 25 5
• Annual breast MRI starting at ages 30-35 years and annual mammography starting at age 40 may significantly reduce breast cancer mortality 1

Pancreatic Cancer Surveillance

• Consider surveillance for carriers with a family history of pancreatic cancer in first- or second-degree relatives 1
• The American Society of Gastroenterology recommends considering pancreatic cancer screening even without family history, though evidence quality is low 1

Prostate Cancer Surveillance

• Should be considered for male carriers 3
• Specific protocols should follow country-specific guidelines 3

Clinical Management Considerations

• Risk-reducing mastectomy is generally not recommended for unaffected female ATM heterozygotes 1
• Radiation therapy decisions for cancer patients with ATM mutations should not be influenced by their carrier status 3
• Conventional therapies can be effective in metastatic cancer in men with ATM mutations and should be considered before PARP inhibitors, which show limited efficacy 1
• All carriers should be made aware of lifestyle factors that contribute to cardiovascular diseases and diabetes 5

Genetic Testing and Counseling

• ATM is a large gene with many variants of uncertain significance (VUS) 1
• Clear language on variant pathogenicity and predicted penetrance should be included in reporting 1
• VUS in ATM should not be used to guide clinical management or for predictive genetic testing for family members 1
• Variant reclassification may occur over time, potentially altering clinical actionability 1

ATM mutations represent an important genetic factor in cancer risk assessment and management, requiring careful consideration of personal and family history for appropriate surveillance and intervention strategies.