NTHL1 Gene Mutation and Cancer Risk: What to Know

What is the NTHL1 Gene?

NTHL1 is a human gene that codes for an important DNA repair enzyme called endonuclease III-like 1. This enzyme helps fix damage that occurs to DNA over a lifetime through chemical exposure, radiation, inflammation, and routine cellular processes.

DNA Damage and Repair

DNA accumulates thousands of damaging events daily that must be fixed to maintain the integrity of the genetic code. Unrepaired DNA damage can result in cell death or mutations that lead to cancer.

Endonuclease III-like 1 enzyme scans DNA strands looking for damaged nitrogenous bases. It snips out the damaged bases so they can be replaced with normal ones during DNA replication and repair.

Oxidative Damage

One major threat to DNA is oxidative damage from reactive oxygen species generated during normal metabolism and inflammation. This can modify DNA bases like guanine into 8-oxoguanine lesions.

The NTHL1 enzyme specifically targets these common 8-oxoguanine lesions and removes them before they can cause GC to TA transversion mutations in DNA.

NTHL1 Gene Mutations

Harmful mutations in the NTHL1 gene can reduce activity levels of the DNA repair enzyme it encodes. This impairs the ability to fix oxidative damage, allowing more unrepaired lesions to build up.

Biallelic Mutations

Inheriting faulty mutated copies of the NTHL1 gene from both parents leads to a condition called biallelic NTHL1 deficiency. This rare recessive disorder causes a neurodegenerative condition called adult-onset leukoencephalopathy.

With no functioning NTHL1 enzyme, oxidative DNA damage accumulates in the brain, leading to neurological decline in adulthood. There can also be increased cancer risk.

Monoallelic Mutations

Inheriting just one mutated NTHL1 copy from either parent causes monoallelic NTHL1 mutation. This more common dominant condition leads to reduced enzyme function but not a complete deficiency.

These individuals have higher levels of unrepaired oxidative DNA damage and are at increased risk for certain cancers but do not develop the neurodegenerative disease.

NTHL1 Mutations and Cancer

Monoallelic NTHL1 mutation carriers have about a 2-fold increased lifetime risk for developing cancer compared to the general population.

Associated Cancers

The cancers most strongly associated with NTHL1 mutations are:

• Colorectal cancer
• Endometrial cancer
• Breast cancer
• Prostate cancer
• Bladder cancer
• Lung cancer
• Ovarian cancer

There are also preliminary links with cancers of the stomach, pancreas, brain, blood (leukemia), and skin (melanoma).

Mechanism of Cancer Risk

Reduced ability to repair oxidative DNA damage likely allows more unfixed mutations to accumulate over time. This genetic instability facilitates tumor development.

Oxidative stress also promotes chronic inflammation, which can nurture a tumor-supporting microenvironment around emerging malignant cells.

Age of Onset

Cancers associated with NTHL1 mutations tend to occur at younger ages, likely because of the lifelong buildup of unrepaired DNA damage. Breast cancer, for example, happens about 8 years earlier on average.

Who Should Be Tested for NTHL1 Mutations?

Genetic testing for NTHL1 mutations may be recommended for certain high-risk groups:

Family History of Biallelic Deficiency

Blood relatives of anyone diagnosed with biallelic NTHL1 deficiency causing leukoencephalopathy should be tested to identify carriers. These individuals are at high risk to have an affected child if their partner is also a carrier.

Early-Onset Cancers

Anyone diagnosed with colorectal, endometrial, breast or ovarian cancer before age 50 should consider NTHL1 mutation testing. Prostate and bladder cancer before age 60 also warrants testing.

Multiple Cancers

Developing multiple primary cancers like two separate breast cancers or breast plus colon cancer points to a possible inherited mutation. NTHL1 mutations increase susceptibility to varied cancer types.

Ethnic Jewish Ancestry

Those with Ashkenazi Jewish heritage have an increased prevalence of NTHL1 mutations estimated up to 1 in 167 people. Genetic testing is recommended for this population.

What Does a Positive NTHL1 Mutation Test Result Mean?

A positive test for a monoallelic NTHL1 mutation indicates an increased but not dramatically high lifetime cancer risk of around 20-30%. Specialized high-risk screening is recommended.

Enhanced Cancer Screening

Carriers should adopt more rigorous screening programs tailored to their gender and family history. This may involve:

• Beginning mammograms or prostate exams 5-10 years earlier
• Shortening intervals between screenings
• Adding supplemental screening modalities like MRI or ultrasound
• Considering risk-reducing surgery at an earlier age

Lifestyle Changes

Living a healthy lifestyle enhances cancer protection by reducing inflammation and free radical production. Tips include:

• Maintaining normal body weight
• Exercising regularly
• Following a antioxidant-rich diet
• Avoiding alcohol and processed meats
• Not smoking

Supplements

Some supplements may help compensate for impaired oxidative damage repair in NTHL1 carriers. Options to discuss with your doctor include sulforaphane, n-acetylcysteine, vitamin C, vitamin E, and curcumin.

What Does a Negative NTHL1 Test Result Mean?

A negative result for an NTHL1 mutation indicates average cancer risk. Standard population-level screening based on age and gender is still recommended.

Continue Routine Screening

All adults should adopt cancer screening practices like:

• Colonoscopy every 10 years starting at age 45
• Annual mammogram starting at 40-45 years old
• PSA blood test for prostate cancer starting at 50
• Pap test every 3-5 years for cervical cancer
• Low dose CT scan for lung cancer if a smoker

Be Cognizant of Risk Factors

Those with a strong family history of cancer, occupational hazards like asbestos exposure, or lifestyle risks like smoking may need to begin screening earlier and more frequently than standard guidelines.

Other Genetic Possibilities

A negative NTHL1 result does not exclude inherited cancer risk entirely. Speak to your doctor about testing considerations for other cancer-linked genes like BRCA1/BRCA2, Lynch syndrome genes, or TP53.

What are the Limitations of NTHL1 Mutation Testing?

Genetic testing has revolutionized cancer risk assessment, but some limitations exist:

Not 100% Sensitive

Current NTHL1 mutation panels do not detect all possible disease-causing variants. Some mutations may be missed, especially in non-coding regions.

Variants of Unknown Significance

Sometimes testing identifies a genetic change with unknown effects on cancer risk. More data is needed to clarify if certain variants are neutral or deleterious.

Reduced Penetrance

NTHL1 mutations show reduced penetrance - not all carriers develop cancer. Environmental and lifestyle factors modify individual risk up or down.

Polygenic Risk

NTHL1 mutations contribute just part of inherited cancer risk. Multiple low-risk gene variants combine with environmental exposures to cause cancer.

Benefits Unproven

It's assumed that knowledge of NTHL1 carrier status improves health outcomes, but studies proving enhanced survival are still needed.

Should Children be Tested for NTHL1 Mutations?

Genetic testing children for adult-onset cancer risk mutations remains controversial. Pros and cons exist.

Arguments For Testing

• Allows early screening and prevention strategies
• Avoids shock later if tested positive as an adult
• Provides information about reproductive risks
• Ends uncertainty if parent is a known carrier

Arguments Against Testing

• May cause distress, anxiety, depression
• Removes right not to know genetic status
• Risks misunderstanding results or overscreening
• Delaying testing allows maturity to cope with information

Overall, there are no established guidelines, and the decision is highly personal. Thorough genetic counseling explores pros and cons for each individual situation.

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a healthcare professional before starting any new treatment regimen.