New Gene Locus Linked to Lung Cancer Susceptibility

Nature Genetics

Genotyping is a rapidly growing research tool in cancer, and many studies have identified candidate areas for cancer susceptibility on various genes. A recent study in has identified another possible locus for an individual’s susceptibility to lung cancer at 5p15.33.

“Since we have been able to study the whole genome, scientists have been looking for various chromosomal and genetic differences between individuals that explain why one person gets cancer and another does not,” said co-author Gary Goodman, MD, from the Fred Hutchinson Cancer Research Center and Swedish Cancer Institute in Seattle, Washington. “Studies like this for almost every tumor type are now possible because genome-wide analysis is relatively cheap.” Dr. Goodman also noted that the large cohorts included in genome studies allow for “statistically robust” analyses.

Under the leadership of James D. McKay of the International Agency for Research on Cancer in Lyon France, the multinational group genotyped 3259 patients with lung cancer and 4159 individuals used as controls. After eliminating data from individuals who did not meet inclusion criteria, the researchers analyzed 315,194 single nucleotide polymorphisms (SNPs). SNPs are DNA sequence variations that arise when a single nucleotide (A, T, C, or G) in the genome sequence has mutated.

Researchers identified 8 SNPs that exceeded the genome-wide significance levels of the study’s protocol. Seven were located at 15q25.1, in an area already known to be associated with lung cancer. The eighth was located on 15p15.33, a potential new locus of susceptibility to lung cancer. Two uncorrelated disease markers were also found at that location.

“This study found a significant genetic difference between individuals that had lung cancer compared to those who did not,” said Dr. Goodman. “These SNPs are in areas of the genome that are not completely defined but may explain some of the differences in a person’s susceptibility to lung cancer,” he added. Dr. Goodman cautioned that the significance of these findings and the potential genetic interactions are not yet fully understood

The 5p15.33 locus contains 2 known genes, of which human telomerase reverse scriptase (TERT) is probably the most interesting. TERT is the reverse scriptase component of telomerase, essential for telomerase enzyme production and maintenance of telomeres. Up to 90% of human tumor samples show telomerase activity, suggesting that regeneration of telomeres is an important step in most forms of carcinogenesis.

The other gene in this locus is the cleft lip and palate transmembrane 1 like (CLPTM1L) gene. This area was identified during screening for genes related to cisplatin resistance and found to be upregulated in cisplatin-resistant ovarian tumor cell lines. The authors of the study thought that given the current understanding of the role of these genes, TERT is probably the more likely culprit in lung cancer development.

“One of the problems of these genome-wide analyses is that they are still very much exploratory,” explained Dr. Goodman. “We don’t yet have a good understanding of the underlying mechanisms.” He noted that researchers have not established how a particular genetic variation contributes to cancer formation. “As the science exists now, it is very important to remember the adage that correlation is not the same as causation. We hope to eventually make the link with causation, but we are not there yet,” he said. As these studies get increasingly larger and more correlations are observed, researchers hope that scientists will study the genetic variabilities more closely to determine why an abnormality in a particular gene makes someone more susceptible to lung cancer (or other diseases).

Currently researchers can only describe where the genetic differences are located. “We currently know there’s a problem in a specific neighborhood,” Dr. Goodman said, using a metaphor to help explain. “We know what block the problem is on, but we don’t in which of the 10 or 15 houses [genes] on the block the problem is. Once we identify the specific gene and its protein product, we’ll need to figure out why the genetic variation increases the chance of getting cancer.”

The newly identified locus happens to be located in an area that includes a cluster of nicotinic acetycholine-receptor genes. “Obviously, nicotine receptors are very much involved in tobacco addiction,” Dr. Goodman noted. “Nobody has yet explained how this leads to lung cancer, but it maybe that these receptors are different in people who do get lung cancer.”

The ultimate goal, according to Dr. Goodman, is to some day be able to do genetic analysis to tell people whether their genetic profile them at especially high risk for certain kinds of cancer. This would allow healthcare professionals to counsel at-risk individuals on modifiable risk factors and suggest interventions that might help prevent cancer or screenings to aid in identifying disease at a much earlier stage. The goal of individualizing treatment according to a patient’s genetic analysis is likely years or even decades from being realized.

Another concern about implementing the widespread use of preventive genetic screening is cost. Although the costs of genetic analysis have declined to where it is affordable in the research setting, achieving extensive clinical use would require steeper price reductions. Dr. Goodman said that the time involved was also a limiting factor in the usefulness of genetic screening.

Dr. Goodman does think genetics may eventually play a more significant role in oncology than in many other specialties. For example, it has already been ascertained that chronic myelogenous leukemia stems from a genetic defect; existing drugs are almost curative, which means that identifying those at risk through genetic analysis could save lives.

Dr. Goodman also pointed out that there are strong indications that genes influence how well some cancer chemotherapy medications work, another example of how advantageous widespread use of this technology could be to the oncology field. He remains cautious, however. “We need to remember that we don’t know what all this means, yet.” He concluded that knowing what you do not know is just as important to scientific progress as what you do know.

Nat Genet

McKay JD, et al. Lung cancer susceptibility locus at 5p15.33. . 2008 Nov 2. [Epub ahead of print]