Data Mine Demonstrates Heredity of Lung Cancers

Lisa A. Cannon-Albright, PhD

By tracing Utah’s genealogy back to its founders, Lisa A. Cannon-Albright, PhD, has been able to identify the subset of family pedigrees with the greatest predisposition to lung cancer, arming investigators with the potential to uncover genetic components of the disease and inform prophylactic measures.

“I'm a really strong believer in the collection of family history. The presence of a positive family history for lung cancer is an indication of increased risk [for the disease],” said Cannon-Albright. “If clinicians identify a positive family history, they should give prophylactic advice and ensure patients stay on an appropriate screening schedule.”

Due to confounding environmental factors in close relatives, such research can be challenging to conduct on a large scale, she added. However, access to Utah’s genealogy has enabled investigators to look at distant relatives and separate environmental factors, such as smoking and radon exposure, from genetic factors.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Cannon-Albright, adjunct professor, Family and Preventative Medicine, professor, Internal Medicine, University of Utah School of Medicine, and chief, Genetic Epidemiology, University of Utah, discussed her research regarding the heredity of lung cancer, histologic subgroups at increased risk, and the implications these data have on practice.

OncLive: Could you discuss your research regarding the genetic components of lung cancer?

Cannon-Albright: I'm a statistical geneticist, so I ask questions pertaining to genetic data. Utah has very unique data. I came here 40 years ago because we have a cancer registry that links the state’s genealogy from its founders to current day. Those data allow you to look at familial clustering and to test genetic hypotheses. Lung cancer has a genetic contribution. I tried to tease out the subgroups to see whether [that contribution] differs by histology, smoking status, or both. We [identified a subset of cancers] that appear to have a strong inherited component. [My research] focuses on those cases and those pedigrees to find the genes responsible [for risk].

Could you elaborate on those subsets?

I did this work with my collaborator Wallace Akerley, MD, of the University of Utah. We split [lung cancers] into small cell lung cancers (SCLC) and non—small cell lung cancers (NSCLC). We divided the cases of NSCLC into squamous and nonsquamous histologies. By and large, the majority of patients with [lung cancer] are smokers. It's a huge risk factor, but [we did] identify individuals with lung cancer who never smoked.

In the 1980s, Utah became the first state to add a question regarding tobacco use to death certificates. Death certificates in Utah are also linked with the state’s genealogy. In approximately half of lung cancer cases [reported in Utah] I can find the person’s death certificate and determine whether the clinician felt that tobacco contributed to the cause of death.

We also split the smokers and nonsmokers into these histologic subgroups. In SCLC, [we demonstrated that] familial effects are largely caused by familial smoking in close relatives. In nonsmoking, nonsquamous NSCLC, there is a clear signal of a genetic contribution. As part of this analysis, we [were able to] identify specific high-risk pedigrees to study further.

What are some other hereditary factors of lung cancer?

Lung cancers are different from many other cancers because common risk factors are confounded. Smoking can cluster in relatives and families. If lung cancer clusters in a family of smokers, there is confounding [variables] that make it hard to ask the statistical questions we need to ask.

Another major risk factor is radon exposure. The more closely related someone is to a person, the more of their lifetime they've spent in the same environment. Those are probably the biggest risk factors we consider in combination with family history.

Utah has the lowest tobacco use rate in the United States because of the strong Mormon culture. Nevertheless, most patients with lung cancer still have tobacco exposure. We also have high radon exposure in Utah. Two of the major risk factors we see are here are confounded with families. However, in Utah, you can cut away the noise and just look at the signal. If I study a family with statistically more lung cancer than I would've expected, given the age and sex of the individuals, and I can identify nonsmokers, I can get rid of a little bit of that environmental noise. Then, I have a better chance of finding the signal for the gene or genes that are responsible [for the cancer].

Could you discuss the importance of familial data to your research?

I focus on families. Typically, the clinicians [recognize the risk for lung cancer] first because they’ll ask about family history or maybe the patient volunteers that information. Many times, I hear about affected relatives; those kinds of studies are very common and been performed all over the world.

Of the studies we have done in Utah, we can look at more than just close relatives. We have the genealogy that allows us to look at more distant relatives. It gets rid of the noise [that exists between] close relatives who share a lot of stuff besides genes. Cousins, first cousins, and second cousins were not brought up in the same household. They might not share the same occupation or lifestyle, but what they do share is genetics; that’s where we look for signals.

Could this research be done in other states?

There are groups all over that study families with lung cancer. In Utah, I have the advantage of having a genealogy. Most states don't have a genealogy. Moreover, in practice, most patients could tell you their parents’ names and birth dates, maybe even their grandparents’ as well. However, many people [can't]. I know it can be shocking [sometimes]. I know my cousins’ [names and information], but many people don't know their cousins and whether they had cancer or not. [Because of the genealogy, [we can do this research a little more powerfully in Utah.