Causes and Risk Factors of Renal Cell Carcinoma

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Renal cell carcinoma is the most common type of kidney cancer, accounting for roughly 90% of kidney cancer cases. In the United States, there are roughly 74,000 new cases of renal cell carcinoma diagnosed each year.

The incidence of this type of cancer has been increasing over the past few decades, with twice as many cases diagnosed annually today as there were in 1975. It is most commonly found in people between the ages 50 and 70 and occurs more often in men than women.

The risk of developing renal cell carcinoma has been strongly associated with modifiable lifestyle factors, such as smoking, obesity, high blood pressure, and some environmental toxins. As with most cancers, there are also risk factors that cannot be changed such as certain genetic disorders, a family history, and some medical conditions.

This article will discuss the causes and risk factors associated with renal cell carcinoma, and what you can do to reduce your risk.

Scientists doing DNA testing

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Causes

Renal cell carcinoma begins when kidney cells acquire a series of gene mutations that eventually lead to uncontrolled cell growth. Gene mutations that cause cancer can be either inherited from parents (germline mutations) or, much more commonly, acquired at some time after birth (somatic mutations).

It's not known precisely what causes renal cell carcinoma, though several strong risk factors have been identified. Specifically, there is evidence to support tobacco as a direct cause. It's thought that unstable molecules (free radicals) in cigarette smoke can directly cause damage to kidney cells' DNA that leads to the development of renal cell carcinoma.

Common Risk Factors

A risk factor is anything that raises the chance that cancer will develop. Renal cell carcinoma, as with many cancers, is often "multifactorial" in origin. This means that a combination of risk factors may work together to increase or decrease the risk.

Smoking, high blood pressure, and obesity are risk factors thought to account for roughly 50% of renal cell carcinomas.

Other risk factors include the following:

Demographics

The incidence of renal cell carcinoma can vary depending on sex, race, and where a person lives.

Age: The average age of diagnosis for renal cell carcinoma is 64, but this cancer can occur at any age, even in childhood. For those who have genetic predispositions, these cancers arise, on average, 20 years earlier. The age at diagnosis may be changing, with much of the recent increase in cases being in people over the age of 75.

Sex: Renal cell carcinoma occurs more often in men than in women, with roughly two-thirds of cases occurring in men.

Race: In the United States, the incidence of these cancers is highest among Native Americans and Black males vs. White males, with Hispanic and Asian males having the lowest risk. Native American, Black, and Hispanic females also develop these cancers more than White females.

Geography: Globally, North America and Western Europe have the highest incidence of renal cell carcinoma, yet it's thought that the incidence will increase in other regions of the world as they adopt a Western lifestyle.

Smoking

Smoking is thought to be the cause of around 30% of renal cell carcinomas in men and 25% in women. Cigarette, pipe, and cigar smoking are all associated with an elevated risk.

Smoking cigarettes increases the risk of renal cell carcinoma, with more pack years of smoking leading to higher risk. Overall, people who smoke (or former smokers) are 1.5 to 1.6 times more likely to develop the cancer, with those smoking over 20 pack years having double the risk.

Among former smokers, the risk decreases significantly for those who have quit more than 10 years previously, but never returns to normal.

Secondhand smoke (environmental tobacco smoke) is also linked to an increased risk of renal cell carcinoma.

High Blood Pressure

High blood pressure (hypertension) is a significant risk factor for renal cell carcinoma, with an overall doubling of risk found in a U.S. study. Risk was higher for those who had been diagnosed for a longer period of time and for those who had poorly controlled high blood pressure, though the risk remained even for those whose blood pressure was well controlled with medication.

Among Blacks, the presence of high blood pressure appeared to raise the risk further (up to 2.8 times average).

Overweight and Obesity

An elevated body mass index (BMI) is associated with an overall increased risk of renal cell carcinoma.

Being overweight has been primarily linked to renal cell carcinomas in women. But obesity (a BMI greater than or equal to 30) raises the risk in both men and women. Those with a BMI of 35 or greater were found to have a risk 71% higher than people of normal weight.

Chronic Kidney Disease and Dialysis

People with kidney disease, particularly those who are on dialysis, have an increased risk of developing renal cell carcinoma.

Compared to people without kidney disease, those who have acquired cystic disease of the kidneys are up to 50 times more likely to develop renal cell carcinoma. On a positive note, an awareness of the risk often allows these cancers to be found early, when they are most treatable.

The overall prevalence of renal cell carcinoma in people with acquired cystic kidney disease is 19% but is lower in those who have had a kidney transplant (5%). Physicians now believe that kidney transplantation may reduce the risk of developing renal cell carcinoma.

Genetics

Renal cell carcinoma is associated both with several genetic syndromes. Having a family history of renal cell carcinoma roughly doubles the risk of developing the disease, especially in first-degree relatives (parents, siblings, or children). Overall, 4% of renal cell carcinomas are considered to be hereditary.

Environmental Toxins/Occupational Exposures

A number of environmental toxins have been linked to renal cell carcinoma, though some of these are better documented than others. Many are from occupational exposure. It's believed that this connection is due to the kidneys being damaged (and cells being altered during repair) as they remove toxins from the body.

Chemicals associated with renal cell carcinoma include:

  • Benzene and benzidine (found in gasoline, textiles, and paints)
  • Cadmium (found in batteries, paints, and welding materials)
  • Metal degreasers
  • Some herbicides (used in agriculture)
  • Trichloroethylene (most often by dry cleaners, mechanics, oil processors, polyvinyl chloride manufacturers, and low-nicotine tobacco producers)
  • Vinyl chloride (used to make plastic)
  • Possibly other chemicals such as lead, asbestos (heat-resistant mineral used in insulation), and polycyclic aromatic hydrocarbons (found in coal, oil, and gasoline), and other solvents

Some Medications

In North America, Europe, and Australia, regular use of Tylenol (acetaminophen) and nonsteroidal anti-inflammatory medications (NSAIDS) such as Advil or Motrin (ibuprofen) has been found to significantly raise the risk of renal cell carcinoma. No increase in risk was identified, however, for the regular use of aspirin (though studies in other regions of the world have suggested a risk).

Similar to environmental toxins, these medications are metabolized/detoxified by the kidneys and may cause cell damage as they are processed. In addition, NSAIDS prevent the production of lipids called prostaglandins, which play a role in kidney function.

Birth Control Associated With Lower Risk

Both hormone replacement therapy and oral contraceptives (birth control pills) have been associated with a lower risk of renal cell carcinoma. Looking at signaling pathways, estrogen may be a factor in the lower incidence of the cancer in women than in men.

Recap

Risk factors that are associated with renal cell carcinoma include smoking, being overweight or obese, having high blood pressure, occupational exposure to certain chemicals, having kidney disease, and regularly taking certain pain medications, including NSAIDs and acetaminophen.

Genetics

Around 4% of renal cell carcinomas are thought to be related to either a family history of the disease or genetic syndromes associated with the disease. Renal cell carcinomas that are hereditary (familial cancers) often occur at an earlier age and may involve both kidneys rather than one.

There are over 10 genetic syndromes associated with renal cell carcinoma. Some of these include:

  • Von Hippel-Lindau syndrome (VHL): This is a hereditary mutation of the VHL gene (a tumor suppressor gene). People with VHL have a 69% chance of developing renal cell carcinoma before the age of 60.
  • Hereditary papillary renal carcinoma (HPRCC): Hereditary mutations in the MET gene are associated with renal cell carcinoma (papillary renal cell carcinoma). While people with this condition have a high risk of developing renal cell cancer (and often more than one), the syndrome isn't associated with other cancers/tumors as many of the others are.
  • Hereditary Leiomyomatosis and renal cell carcinoma: This syndrome is caused by a mutation in the fumarate-hydratase (FH) gene and is linked to papillary type 2 renal cell carcinoma. People with the syndrome have a roughly 16% chance of developing the cancer. It is also associated with a number of other tumors.
  • Birt-Hogg-Dubé syndrome (BHD): BHD syndrome is caused by a hereditary mutation in the BHD gene that makes a person open to getting renal cell carcinoma. It is associated with a number of other tumors as well.
  • Succinate dehydrogenase (SDH) complex syndrome: SDH syndrome is a group of syndromes related to mutations in the SDHB and SDHC genes associated with renal cell cancer (several types), as well as other tumors such as pheochromocytoma.
  • BAP1 tumor predisposition syndrome: Breast cancer gene (BRCA) associated protein-1 (BAP1) mutations are linked to clear cell renal cell carcinoma.
  • PTEN hamartoma syndrome (Cowden syndrome): Mutations in the PTEN gene are associated with clear cell renal cell carcinoma.
  • Tuberous sclerosis complex syndrome: Roughly 2%–4% of people with tuberous sclerosis will develop renal cell carcinoma.

Lifestyle Risk Factors and Prevention

A number of lifestyle factors may either increase or decrease the risk of developing renal cell carcinoma. While people can't control their age or genetics, lifestyle factors are something that can be modified to reduce risk.

In fact, it's been found that three of these factors can be aggressively targeted to reduce the risk of developing the disease including:

  • Avoiding or quitting smoking: Quitting at any time helps, but the risk drops significantly 10 years after quitting.
  • Managing high blood pressure: Newer evidence suggests that controlling blood pressure can reduce risk.
  • Maintaining a healthy body weight: Keeping excess weight off can reduce the risk. In particular, regular physical activity (in addition to a healthy diet), which can help with weight loss, was found to reduce the risk of renal cell carcinoma by 22%.

Each of these risk factors is considered "dose dependent," meaning that even small efforts to manage the risk factor might reduce risk. Certainly, greater management could reduce risk even further.

Other Potentially Modifiable Risk Factors

Eating a healthy diet: Studies have found that a diet high in vegetables (especially cruciferous varieties, such as broccoli, Brussels sprouts, cabbage, and kale), fiber-rich legumes (beans), and fruits are associated with a lower risk of some types of renal cell carcinoma. Contrarily, a diet high in meats and dairy products may elevate risk.

Moderate alcohol consumption: Moderate alcohol consumption has been associated with a lower risk of developing renal cell carcinoma.

Reducing the use of certain medications: Since NSAIDs are associated with an elevated risk of renal cell carcinoma, it may be helpful to talk to your healthcare about alternative methods of managing pain and discomfort, if you use these medications regularly.

Occupational exposures: Employers are required to notify workers of carcinogens they may be exposed to and provide material data safety sheets as to their proper use and protection. Make sure to take the time to read these to learn of specific precautions you should take, including wearing gloves, masks, and respirators, or limiting time of exposure.

Managing kidney disease: It's important to see your healthcare provider regularly, having blood work to test your kidney function to catch and treat any problems early. For those who have advanced kidney disease, careful monitoring is also needed.

Genetic testing and screening: Talk with your healthcare provider about your cancer risk if you have kidney cancer in your family or have any of the genetic syndromes associated with the disease. With some, such as VHL syndrome, your healthcare provider may want to order regular screenings to look for cancer periodically.

Summary

Like most cancers, there is no known cause of renal cell carcinoma. However, there are known risk factors, including smoking, obesity, and having high blood pressure. Other risk factors include occupational chemical exposure, overuse of certain pain medications, and genetic cancer syndromes.

The most important changes you can make to reduce your risk of developing this cancer are quitting smoking, managing your high blood pressure, and maintaining a healthy weight with a nutrient-rich diet and regular exercise.

A Word From Verywell

Fortunately, many of the known risk factors for renal cell carcinoma are considered modifiable—they can be changed to lower your risk. What's more, being aware of factors that cannot be changed, such as a family history of the cancer, may help you and your healthcare provider be proactive in detecting any cancer that might develop at the earliest and most treatable stage possible.

With any medical condition, it's important to be your own advocate and adopt health-promoting habits. With renal cell carcinoma, your efforts can make a difference in reducing your risk. There are many factors in life you can't change, so it's refreshing to have some control. While changing any risk factors you have might seem overwhelming, even small positive changes can help protect your health over the long run

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