What is the relationship between the Ataxia-Telangiectasia Mutated (ATM) gene and thyroid cancer risk?

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The ATM Gene and Its Relationship to Thyroid Cancer Risk

The ATM (Ataxia-Telangiectasia Mutated) gene is associated with an increased risk of thyroid cancer, particularly through specific polymorphisms that can affect individual susceptibility to differentiated thyroid carcinoma. 1

What is the ATM Gene?

The ATM gene is located on chromosome 11q22-23 and encodes a nuclear protein with a critical phosphatidylinositol 3-kinase (PI3K) domain at its carboxy terminus 2. This gene plays several essential roles in cellular function:

  • DNA damage response: ATM is activated in response to ionizing radiation-induced DNA damage
  • Cell cycle checkpoint regulation: Controls cell cycle progression when DNA damage is detected
  • DNA repair: Facilitates repair of damaged DNA
  • Apoptosis regulation: Helps determine whether damaged cells undergo programmed cell death

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

  • Progressive cerebellar ataxia
  • Oculomotor apraxia
  • Oculocutaneous telangiectasia
  • Variable immunodeficiency 3

ATM Gene and Thyroid Cancer Risk

The relationship between ATM gene variants and thyroid cancer has been demonstrated in several studies:

Specific Polymorphisms and Thyroid Cancer Risk

Research has identified specific ATM single nucleotide polymorphisms (SNPs) that affect thyroid cancer susceptibility:

  • The G allele of ATM rs189037 shows a protective effect against differentiated thyroid carcinoma (DTC) with an adjusted OR = 0.8 (95% CI, 0.6-1.0; P = 0.04)
  • The G allele of rs1800057 is associated with increased risk of DTC with an adjusted OR = 1.9 (95% CI, 1.1-3.1; P = 0.02)
  • A specific haplotype (A-G-C-T-C-A) was associated with decreased risk of DTC in non-Hispanic whites 1

Cumulative Risk Effect

A significant dose-response relationship exists between the total number of risk alleles in the ATM gene and differentiated thyroid carcinoma risk:

  • Carriers of 6-7 risk alleles have a 30% increased risk (adjusted OR = 1.3; 95% CI, 1.0-1.7)
  • Carriers of 8-10 risk alleles have a 50% increased risk (adjusted OR = 1.5; 95% CI, 1.1-2.1) 1

Case Reports

There have been documented cases of thyroid cancer in patients with ATM mutations:

  • A 13-year-old girl with A-T developed papillary thyroid carcinoma with follicular variant, requiring thyroidectomy and radioiodine therapy 4

ATM Missense Mutations and Thyroid Cancer

In a large prospective study following 10,324 individuals from the general population for 36 years:

  • The ATM Ser707Pro heterozygous mutation was associated with a 10-fold increased risk of thyroid/other endocrine tumors (HR = 10; 95% CI, 1.1-93) 5

Clinical Implications

Testing for ATM Variants

The p53 mitotic centrosomal localization (p53-MCL) test in peripheral blood mononuclear cells has been validated as a reliable and specific test for detecting germline ATM variants 6. This test is:

  • Straightforward
  • Rapid
  • Inexpensive
  • Able to diagnose mutant ATM zygosity

Cancer Surveillance

For individuals with identified ATM germline pathogenic variants (GPVs):

  • Breast cancer surveillance should follow country-specific guidelines (ATM is primarily known as a breast cancer susceptibility gene with a 2-fold increased risk) 3
  • Prostate cancer surveillance should be considered due to moderate risk association 3
  • Pancreatic cancer surveillance should be considered based on family history 3
  • Thyroid cancer screening may be warranted, particularly for those with specific risk alleles or missense mutations like Ser707Pro 5

Limitations and Considerations

  • Some associations between ATM variants and specific cancer types may represent chance findings due to multiple comparisons in studies 5
  • The relationship between ATM and thyroid cancer needs further confirmation in independent studies 1
  • ATM's role in cancer susceptibility appears to be complex, with different variants potentially affecting risk for different cancer types

Research Gaps

Systematic prospective data collection is needed to:

  • Better establish the full spectrum of ATM-associated cancers
  • Determine optimal surveillance protocols
  • Understand treatment responses and survival outcomes 3

References

1
Research

Functional variations in the ATM gene and susceptibility to differentiated thyroid carcinoma.

The Journal of clinical endocrinology and metabolism, 2012

2
Research

[ATM and Cancer].

Zhongguo shi yan xue ye xue za zhi, 2002

3
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

5
Research

Risk of cancer by ATM missense mutations in the general population.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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