Inherited Susceptibility to Lung Cancer: What Do We Know?

In 2013 it is estimated that there will be 228,190 new cases and 159,480 deaths due to lung cancer in the United States,¹ making it the leading cause of cancer-related death. In fact, it causes more deaths than colon, breast, and prostate cancer combined.² Two main lung cancer histologic subtypes exist: small cell and non-small cell, with each having different clinicopathologic characteristics. The most common type is non-small cell (7 of every 8 people),³ which includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Most often lung cancer occurs when people breathe in dangerous, toxic substances. It is believed that smoking causes lung cancer by damaging the cells lining the lungs; as such, cigarette smoking is the primary risk factor for lung cancer. Other risk factors include exposure to radon or secondhand smoke, certain smoking-related diseases, and occupational exposure to lung carcinogens, such as asbestos, arsenic, nickel, and chromium.^4,5

For many years, scientific evidence has strongly demonstrated the association of cigarette smoking with lung cancer. It is well established that the risk increases based on the number of years an individual smokes as well as the quantity he or she smokes. For never-smokers (typically defined as individuals who have not smoked 100 cigarettes in their lifetime), exposure to secondhand smoke and workplace carcinogens are the 2 biggest risk factors; however, approximately a fourth of never-smokers with lung cancer worldwide report no exposure to either.⁶ Of note, although most patients with lung cancer (at least 80%) have used tobacco products, only about 20% of long-term heavy smokers will develop the disease.⁷ Moreover, many people with lung cancer have never smoked, and having a family history of lung cancer increases a person’s risk as well. This tells us that genetic factors may make certain individuals more prone to developing lung cancer—even in the smoking population.

An association between family history and lung cancer risk has been reported since at least the 1960s8 and continues to be demonstrated. Individuals with a first-degree relative with lung cancer are at an approximate 50% increased risk of developing lung cancer compared with those without a family history.⁹ The association appears to be greater when a sibling rather than a parent is affected. For those who have ever smoked and have a first-degree relative with lung cancer, the increased risk is approximately 3.19 compared with never-smokers without a first-degree relative with the disease. The risk also appears to increase when lung cancer has been diagnosed in an affected family member under age 50 years and when multiple family members are affected. Thus, a positive family history may be one inclusion criteria for studies focused on lung cancer screening.

Although a relationship has been demonstrated between family history and lung cancer for 50 years, little is known about the genetic influences involved. Familial studies display high heterogeneity, and it is challenging for researchers to account for environmental exposures such as smoking. Not only does an individual’s exposure influence the risk of developing lung cancer, it also likely affects his or her genetic capacity to activate or inactivate tobacco carcinogens.¹⁰ Furthermore, the overall 5-year survival rate is much lower than other cancers, around 16.6%, and only approximately 15% of cases are diagnosed at an early, localized stage.¹¹ As a result, it is difficult to ascertain survivors for research studies, especially families with multiple lung cancer survivors.

In the past several years, chromosome regions that may help explain variation in lung cancer risk have been identified. Genome-wide association studies have reported chromosomal region 15q24-25.¹ as associated with an increased risk of lung cancer,^12-15 as well as 5p15, 6p21-6p22, and 12p13.¹² Linkage analyses in families with lung cancer have also shown a region of 6q23-25 as associated with an increased risk.^10,16,17 In addition, variation in 9p21.³ may be associated with squamous cell lung cancer risk.¹² However, none of these regions have yet proven useful in a clinical setting.

To date, there isn’t one specific susceptibility gene that explains most cases of familial lung cancer. However, there are several genetic syndromes that may place an individual at an increased risk of developing lung as well as other cancers. These include Li-Fraumeni syndrome, retinoblastoma, xeroderma pigmentosum, and Peutz-Jeghers syndrome.

Of the syndromes, Li-Fraumeni has the most well-documented association with lung cancer risk. This syndrome is associated with mutations in the TP53 gene. Individuals are primarily at an increased risk for sarcomas, breast cancer, brain tumors, adrenocortical carcinoma, and leukemias. Other reported cancers include lung, gastrointestinal, genitourinary, skin, thyroid, and neuroblastoma.^18,19

Retinoblastoma is associated with mutations or deletion of the RB1 gene. Like Li-Fraumeni syndrome, this condition is transmitted in an autosomal dominant manner. Individuals are at high risk of developing retinoblastoma before age 5 years and also at increased risk for melanoma.^20,21 Other reported cancers have included osteosarcomas, soft tissue sarcomas, brain tumors, lymphoma, and breast as well as lung cancer.^21,22

Xeroderma pigmentosum is associated with mutations in several genes and is inherited in an autosomal recessive manner.²³ It causes extreme sensitivity to ultraviolet rays and results in a high risk of developing skin cancer. Other reported associated cancers have included brain and lung (in smokers).²⁴

Peutz-Jeghers syndrome is associated with mutations in the STK11 gene and is inherited in an autosomal dominant fashion. Individuals are at increased risk for gastrointestinal polyposis, mucocutaneous pigmentation, and a variety of cancers including colorectal, gastric, pancreatic, breast, ovarian, and adenoma malignum of the cervix.²⁵ Somatic mutations in STK11 are common in lung cancer.^25,26 Some studies and/or case reports have shown an association with STK11 germline mutations and lung cancer risk. However, similar to retinoblastoma and xeroderma pigmentosum, the association has not been routinely replicated and/or did not account for cigarette smoking and, thus, the true association remains unclear.

Take-Home Messages

• Knowledge surrounding inherited lung cancer susceptibility is in its infancy
• Although studies have shown an association between family history and risk of lung cancer, little is known about the genetic influences involved. Gene variants involved in lung cancer have been identified in the past several years; however, the significance of these findings to increased risk remains unclear and a single “lung cancer gene” has not been identified
• Because identifying individuals who are at increased risk of lung cancer is imperative for prevention and screening studies, encourage patients with lung cancer and their family members to participate in research studies assessing inherited risk factors

References
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