Relation, Heredity, and Other Genetic Factors for Lung Cancer

How family history affects lung cancer risk

Paper house with paper family illustrating hereditary lung cancer

ashumskiy/istockphoto

Hereditary lung cancer is something discussed less of than, say, hereditary breast cancer, but just like many other cancers, lung cancer can run in families. Research has only recently begun to identify some genes that are associated with an increased risk, but there is much more to be learned. Overall, it has been estimated that 8% of lung cancers are hereditary or occur as a result of a genetic predisposition. A hereditary component is more likely to be present in lung cancer in young adults, never smokers, and women who develop the disease.

We will look at how having a family history of lung cancer increases risk, characteristics of familial lung cancer, and some genetic associations that have been discovered.

Lung Cancer Can Run in Families

While many people think of lung cancer as a "smoker's disease," it can run in families and does occur in people who have never smoked. In fact, lung cancer in never smokers is currently increasing in both the United States and Europe. Based on the molecular characteristics of tumors in never smokers, it is not secondhand smoke that is responsible for the increase. The chance that having a family history of lung cancer may increase your risk (whether you smoke or have never smoked) depends on how closely you are related and other factors.

How Closely a Family Member is Related

Having a first-degree family member (parent, sibling, or child) with lung cancer roughly doubles the risk of developing lung cancer. This risk is greater for women than men, and stronger in nonsmokers than smokers. Having a second-degree relative (an aunt, uncle, niece, nephew, or grandparent) with lung cancer increases risk by around 30 percent.

Risk is increased further if more than one family member has had lung cancer, especially if any of the family members were young at the time of diagnosis, female, or never smoked.

Race

Blacks with first-degree relatives who have had lung cancer have a greater risk of early-onset lung cancer than whites. This risk increases further in those who smoke.

Characteristics of Familial Lung Cancer

There are a number factors that may suggest lung cancer has a hereditary component. These include:

Age

People who develop lung cancer at a younger age are more likely to have a genetic predisposition to the disease. The average age for lung cancer at current time is 71. Even if someone smoked, but is only age 50, this is true.

Sex

Men and women are about equally likely to develop cancer at the current time. Lung cancer in women, however, is more likely to have a genetic component. Women are also more likely to develop lung cancer at a young age.

Geography

In some regions of the world, familial lung cancer appears to be much more common than others. For example, in Xuanwei City in the Yannan Province of China, the incidence of hereditary lung cancer is very high.

Smoking Status

Smokers who develop lung cancer are less likely to have a family history than ​non-smokers who develop lung cancer. That said, however, for those who have a genetic predisposition to lung cancer, smoking appears to amplify that risk.

With smoking there is also the concept of the latency period, or the time between exposure and development of cancer. If a person has smoked, but is young, it's likely that risk factors other than smoking played at least some role in the development of the tumor. This is also true when people have fewer pack years of smoking, for example, if a person smoked for 10 years as a young adult and then quit.

Multiple Lung Cancers

People who develop more than one primary lung cancer (second unrelated lung cancers) are significantly more likely to have a genetic predisposition contributing to their cancer.

Type of Lung Cancer and Heredity

Studies vary in the types of lung cancers that have the greatest hereditary component, but those with nonsmall cell lung cancers, especially lung adenocarcinoma are more likely to have a family history of lung cancer (a genetic predisposition) than those with small cell lung cancers.

Tumor Genomics

A recent finding is that non-smokers with non-small cell lung cancer whose tumors have EGFR mutations are much more likely to have a family history of lung cancer than those who have an ALK rearrangement or KRAS mutation.

Genetics vs.The Environment

Lung cancer can run in families, but to determine the role that genetics play, it's important to separate out other common factors that might be responsible. For example, common exposures in the home (such as radon) or common lifestyle factors (such as smoking) could make lung cancer appear to have a hereditary component.

For this reason (to distinguish between nature and nurture), scientists have run controlled studies to determine how much of the risk is related to common genetics alone rather than other factors.

The actual roles of genetics vs. the environment in lung cancer risk is actually much more complicated. For example, a person's genetic make-up may render them more susceptible to certain carcinogens in the environment. In addition, while researchers have been looking for specific genetic changes such as gene mutations, a combination of different genes may be associated with risk rather than any specific alteration.

Hereditary Gene Mutations and Familial Lung Cancer

Just as BRCA gene mutations have been found to increase breast cancer risk, researchers are beginning to uncover gene alterations that may raise the risk of lung cancer.

Hereditary (Germline) vs. Acquired (Somatic) Gene Mutations

When talking about gene mutations, it's important to define two things. Most mutations physicians talk about when genetic testing (genomic testing) is done for lung cancer are somatic or acquired mutations. These mutations are not present from birth, but rather occur in the process of a cell becoming a cancer cell. They are only present in cancerous tissue and can not be passed down to offspring.

In contrast, hereditary or germline mutations are passed from parents to children. They are present in every cell of the body, not just cancer cells.

Hereditary Gene Mutations Don't Cause Lung Cancer

With hereditary gene mutations that raise the risk of lung cancer, the gene mutation (or the protein coded for by the gene) does not itself cause lung cancer. Instead, it confers a genetic susceptibility.

Many hereditary gene mutations that raise cancer risk are found in genes known as tumor suppressor genes. These genes code for proteins that repair damaged DNA in cells (such as damage caused by carcinogens in the environment or produced as byproducts of the normal metabolism of cells), or eliminate cells that cannot be repaired. Damaged cells that are neither repaired or eliminated may continue to survive to develop into cancer cells. BRCA genes are examples of tumor suppressor genes.

This interaction between genetics and the environment explains why not every with a particular gene mutation, even high penetrance mutations such as BRCA mutations, develops cancer. It's important to note that it's not usually a single mutation, but a series of mutations in both tumor suppressor genes and oncogenes that leads to cancer.

Breast Cancer Gene (BRCA2) and Risk of Lung Cancer

It's been found that people who have a BRCA2 gene mutation, one of the mutations found in people with genetic breast cancer, are at a higher risk of developing lung cancer as well. This mutation is found in roughly two percent of people of European ancestry and is inherited in an autosomal dominant fashion (if one of your parents carries the mutations, you have a 50:50 chance of inheriting it yourself).

In addition to increasing the risk of breast cancer and ovarian cancer (among others), smokers who have a BRCA2 mutation were found to have almost twice the likelihood of developing lung cancer. (The risk of lung cancer was also higher than normal for non-smokers with the mutation.) Smokers carrying this mutation appeared to have an increased risk primarily for squamous cell lung cancer, a form of non-small cell lung cancer. At this time, there are not any specific recommendations regarding screening for people with the mutation, but those who are concerned may wish to talk to their physicians about the possibility of CT screening if they have any other risk factors for lung cancer, such as a history of smoking or exposure to radon in their home.

The research is young, but the unveiling of the human genome is allowing researchers to look for genetic changes in addition to BRCA2 mutations that may raise lung cancer risk. It's likely, that in the future, genetic testing may give important information on who is at risk for lung cancer, so that appropriate screening and monitoring can be done.

Other Gene Mutations and Lung Cancer Risk

Thus far, only a few gene mutations have been found to be associated with lung cancer, but the science is young relative to other cancers. Studies known as genome wide association studies will hopefully shed more light. For example, these studies have found that a common sequence on chromosome 15 (15q24-25) is associated with both lung cancer and nicotine dependence.

Overlap Between Somatic and Germline Mutations in Lung Cancer: EGFR T790M

Most commonly, people who have EGFR positive lung cancer will develop a T790M resistance mutation after treatment. In this case, the new mutation allows the cancer cells to bypass the pathway blocked by EGFR inhibitors and grow again.

If EGFR T790M is present prior to treatment, however, there is roughly a 50 percent chance that it is a germline mutation (an inherited mutation) rather than a mutation acquired in the process of a cancer developing (somatic mutation).

If You Have a Family History of Lung Cancer

If you have a family history of lung cancer you may be able to reduce your risk of dying from the disease.

For those who smoke or have smoked in the past, CT screening for lung cancer is an option. It is currently recommended for people between the ages of 55 and 74, who smoke or have quit in the past 15 years, and have at least a 30 pack-year history of smoking. Depending upon your risk factors, you and your doctor may elect to choose screening outside of these parameters. Lung cancer screening often picks up lung cancers in the earlier, much more curable stages of the disease, and can clearly save lives. Unfortunately, many people who are eligible for screening are unaware of the benefit.

Aside from avoiding tobacco, testing your home for radon, eating a healthy diet, exercising and being careful to avoid occupational causes can all help lower your risk of developing lung cancer whether you have a family history or not.

Was this page helpful?

Article Sources

  1. Kanwal M, Ding XJ, Cao Y. Familial risk for lung cancer. Oncology Letters. 2017. 13(2):535-542. doi:10.3892/ol.2016.5518


  2. Gaughan EM, Cryer SK, Yeap BY, Jackman DM, Costa DB. Family history of lung cancer in never smokers with non-small-cell lung cancer and its association with tumors harboring EGFR mutations. Lung Cancer. 2013. 79(3):193-7. doi:10.1016/j.lungcan.2012.12.002


Additional Reading