Causes and Risk Factors of Adenoid Cystic Carcinoma

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Adenoid cystic carcinoma (ACC) is a type of cancer that invades glands in your body. While rare, ACC is the second most common malignancy or cancer subtype of the salivary gland. Salivary gland ACC develops as cells divide in the salivary glands in your mouth, head, and neck. It’s not known exactly why these cells change.

This article discusses the most widely accepted causes and exacerbating factors. Exacerbating factors are not direct causes but do make you more vulnerable to developing the disease.

Risk Factors for Oral Cancer

Verywell / Jessica Olah

Common Causes

There is no proven cause of adenoid cystic carcinoma. Instead, research shows that there may be some genetic changes associated with the tumor. While some lifestyle risk factors may raise the chance of developing this cancer, none have been definitively identified.

Approximately 80% of ACC patients are diagnosed with a primary (initial) tumor in the head and neck region, 12% in mammary (breast) glands, and the remainder throughout the rest of the body, according to the Adenoid Cystic Carcinoma Research Foundation.

Genetics

Some genes and some combinations or sequences of genes have been associated with ACC. This doesn't mean ACC is inherited. There are actually almost no known cases among members of the same family (only two have been reported). This means ACC isn’t considered a family disease or something that is passed down from generation to generation (you aren’t born with a gene for ACC).

Inherited and Acquired Mutations

There are two kinds of gene mutations (changes in the DNA of the gene). You may inherit an abnormal gene from either genetic parent, in which case you are born with the mutation.

Or, you may develop a mutation as your cells divide during your lifetime. These changes would get passed to your offspring only if they happen in the cells that develop into your sperm or ova. But changes in any cell can disrupt gene functioning (turning it on or off, or activating or deactivating). When this happens, it can lead to disease, including tumors.

MYB-NFIB Gene Fusion

Tumors of most ACC patients have genetic alterations in genes called MYB and MYBL1. These changes are what lead to high levels of the associated proteins that drive ACC tumor growth. The MYB-NFIB gene fusion has been found in about 90% to 95% of ACC tumors examined.

In 2017, a case was reported in the journal Head and Neck Pathology in which a 50-year-old female and their father presented with minor salivary gland ACC. While their tumor shapes were different, the two patients shared a similar gene change associated with ACC. This gene fusion (MYB-NFIB) is demonstrated by fluorescence in situ hybridization (FISH) and RNA-sequencing tests. 

Gene Splicing Events



A study published in February 2021 in the journal Cancer Research identified multiple splicing (dividing/separating) events in genes specific to salivary gland ACC (e.g., the gene called FGFR1). This furthers the understanding of how gene changes and ACC tumors are connected.

NOTCH Gene Family

Around a quarter (25%) of all ACC patients whose tumors return after surgery and radiation have been found to have genetic alterations in the NOTCH gene family that lead to more aggressive disease.

A study published in the Journal of Clinical Oncology in 2017 looked at 102 patient with ACC tumors. They found 18 NOTCH1 mutations in 15 tumors. They also found that two patients had more than one NOTCH1 mutation in their gene code.

The researchers say the majority of NOTCH1 mutations in ACC (91%) are predicted to be activating or revving up those problematic proteins (aka ​​gain-of-function mutations). 

P53 Gene

Other evidence has shown a specific gene called the p53 tumor suppressor gene is somehow inactivated in advanced and aggressive forms of ACC. The p53 gene limits cell growth by monitoring the rate at which cells divide.

This doesn’t mean those genes are the cause of the ACC. It means, though, that there is some connection or correlation between these non-inherited genetic changes and ACC.

Lifestyle Risk Factors 

Different cancer types can have various risk factors. Risk factors are things that increase your risk of developing cancer. According to the American Society of Clinical Oncology (ASCO), most risk factors do not directly “cause” cancer.

Some lifestyle risk factors for cancer, like smoking, can be changed, while other risk factors, like family history, cannot. ASCO says risk factors for ACC have not been proven consistently with scientific research.

One small control study involving 81 patients with major salivary gland cancer published in the journal Cancer found a significant association between cigarette smoking and major salivary gland cancer, though.

General risk factors for oral cancer include:

  • Tobacco use of any kind, including cigarette smoking 
  • Heavy alcohol use 
  • Using tobacco plus alcohol (poses a much greater risk than using either substance alone) 
  • Not eating enough fruits and vegetables regularly
  • Having a weakened immune system
  • Having specific underlying health problems like graft-versus-host disease (a complication of stem cell transplants)

One in vitro (test tube) study from 2015 published in the Journal of Immunology Letters suggests that elevated immune responses and/or secondhand smoke can negatively impact adenoid health. The study looked at 277 children (151 males and 126 females; median age 5.5 years) requiring adenoid surgery (removal or adenoid surgery with tonsil removal).

These risk factors were associated with elevated antibodies that play a crucial role in immune system functioning.

A study published in the journal Clinical Cancer Research in 2020 looked at 76 types of salivary gland tumors, including 22 ACC tumors. They found an association between ACC tumors and immune-depleted microenvironments. This means immune cells that fight disease were not getting inside or infiltrating the tumor cells.

Other types of salivary gland tumors showed more immune cell activity (infiltration). This research shows some association between immunosuppression (overpowered immune system) and ACC tumors.

More research on risk factors is needed.

Summary

The exact cause of adenoid cystic carcinoma is not yet known. Some gene alterations are associated with the tumor, but it doesn't appear to run in families. Lifestyle risk factors such as smoking have not been proven to raise the risk, but they are implicated in oral cancers in general.

A Word From Verywell 

If you’re concerned about developing ACC, you can talk to your doctor or dentist about your personal risk factors. While things like cigarette smoking and alcohol drinking have not been conclusively linked to or outright labeled as specific risk factors for ACC, they are both risk factors for other types of oral cancers.

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