Two Genetic Variants on Chromosome 15 Linked to Familial Lung Cancer
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From: J on 19 Sep 2008 21:05 Two Genetic Variants on Chromosome 15 Linked to Familial Lung Cancer http://www.medscape.com/viewarticle/580464 Jacquelyn K. Beals, PhD September 12, 2008 � Two single nucleotide polymorphisms (SNPs) in a region of human chromosome 15 are associated with increased lung cancer risk, according to a genomewide association study comparing patients who have familial lung cancer with control patients. Strong candidate genes in this region code for nicotinic acetylcholine receptor subunits. The study suggests that a recessive and/or additive mode of inheritance may be involved. Results of the case-control study are published in the September 13 issue of the Journal of the National Cancer Institute. Previous reports in the literature have indicated a genetic basis for lung cancer susceptibility, focusing on such factors as early onset, association with female reproductive cancers, and the families of nonsmokers with lung cancer. Case samples in the present study were collected through the Genetic Epidemiology of Lung Cancer Consortium. Control samples were collected from unaffected individuals who were not related by blood to case patients. SNP genotyping was performed using blood DNA from 194 case patients and 219 control patients. The study found SNPs associated with lung cancer on chromosomes 1, 3, 6, 9, 12, 15, and 20. A strong cluster of SNPs was identified on chromosome 15 � specifically, "a 160 kilobase region at 15q24-25.1." This region on the long arm of human chromosome 15 contains multiple genes, including CHRNA3, CHRNA5, CHRNB4, and PSMA4. Study author Haris G. Vikis, PhD, research assistant professor in the Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, described the findings in his email to Medscape Pathology & Lab Medicine. "It's not unusual to observe several candidate genes from a SNP association study," noted Dr. Vikis. "The broadness of the region is based on a property called linkage disequilibrium...nonrandom association of markers (SNPs) with the true disease locus.... [T]he association signals can cover a distance of up to several hundred kilobases[, and which] of these associated SNPs are markers and which are causal is not so easily determined," Dr. Vikis said. The present investigation confirmed recently reported associations between sporadic lung cancer and 2 SNPs in region 15q25.1. In the current study, rs8034191 and rs1051730 were highly associated with familial lung cancer (odds ratio [OR], 3.84; 95% confidence interval (CI), 1.75 � 8.84; P = 3.74 � 10?4; and OR, 3.43; 95% CI, 1.66 � 7.37; P = 2.90 � 10?4, respectively). The risk of developing lung cancer was increased in individuals with both a family history of lung cancer and 2 copies of high-risk alleles of these 2 SNPs. "Our study suggests that 2 copies of the common allele, in addition to family history, is what increases lung cancer risk 5 to 7 times," said Dr. Vikis. "This risk increase is independent of smoking habits but does depend on family history of lung cancer (whose families have 3 or more first-degree affected members). This is in contrast to previous studies that have suggested a more mild risk increase for individuals with both alleles, and no family history of lung cancer, resulting in risk increases of 0.7 to 0.8 times." Dr. Vikis pointed out that the major risk factor is still long-term smoking, "with risk estimates anywhere between 10 and 20 times." Among the genes in this region of chromosome 15, CHRNA3, CHRN5, and CHRNB4 encode subunits of nicotinic acetylcholine receptors. The authors observe that these genes "may participate in nicotinic addiction through reward pathways in the brain." Studies have already linked these receptors to the development of lung cancer. The study also evaluated several models to determine whether SNPs in 15q24-25.1 that influence lung cancer risk act dominantly, recessively, or additively. The recessive model was strongest, with the risk for lung cancer being higher in homozygotes with the high-risk allele rs1051730 than in those homozygotes with no copies (P = 2.90 � 10?4). The additive model also demonstrated statistical significance for many SNPs in the region. Thomas A. Sellers, PhD, director, Moffitt Research Institute, and associate center director, executive vice president, Division of Population Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, commented via email to Medscape Pathology & Lab Medicine. "It should be pointed out that the published genomewide studies of lung cancer don't fully agree on whether the gene influences smoking (and therefore lung cancer) or lung cancer (independent of smoking). There are plausible reasons why both studies may be correct," said Dr. Sellers. "If what is going on turns out to be the genetic influence is on nicotine response, then the risk of lung cancer is secondary to the nicotine addiction. If...the gene is unrelated to smoking behavior, then some other mechanism may be involved. For example," Dr. Sellers continued, "we now have good evidence that cancer patients who smoke have worse outcomes than cancer patients who don't. There may be similar biological differences that influence risk, rather than response, to tobacco." Dr. Vikis and Dr. Sellers have disclosed no relevant financial relationships. J Natl Cancer Inst. 2008;100(18):1326�1330. http://info.cancerresearchuk.org/cancerstats/types/lung/molecularbiologyandgenetics/ [Excerpt] Lung Cancer molecular biology and genetics No clearly inherited forms of lung cancer have been described, although the disease is occasionally seen in individuals with Li-Fraumeni syndrome, which is caused by inherited faults in the TP53 gene.1 In these cases, the disease develops at an earlier than expected age. Carriers of germ-line mutations in the retinoblastoma gene RB1 are also at an increased risk.2 Although the greatest risk factor for developing lung cancer is smoking, a recent meta-analysis suggests that individuals with a family history of lung cancer are at an increased risk of developing the disease.3 This is particularly true for families with a number of affected individuals and where cases have been diagnosed at a young age. By looking at the incidence data in people who had never smoked, the meta-analysis suggests that there is a genetic component to this increased risk. A susceptibility locus for familial lung cancer has been mapped to chromosome region 6q23-25,4 and recently a candidate tumour suppressor, p34, has been found in this region.5 This gene does not seem to be involved in familial lung cancer susceptibility, but may play a role in sporadic cases of the disease.5 Back to top ^ As many smokers do not develop lung cancer it is likely that inherited factors influence the effects of tobacco. There is considerable interest in variants of genes that help detoxify the carcinogens in tobacco smoke, such as members of the cytochrome P450, GST and NAT gene families.6 The capacity to repair DNA damage is also reduced in people with lung cancer � in the laboratory, cells from lung cancer patients are less able to repair DNA damage caused by chemicals in tobacco than cells from normal individuals.7 Lung cancer progression is characterised by cumulative alterations in key molecules involved in the cell cycle, signalling and angiogenesis pathways. Most lung cancer patients demonstrate chromosomal abnormalities at the site of tumour suppressor genes or have mutations in known oncogenes. Loss of heterozygosity is common, particularly at the chromosome regions 3p (which includes the FHIT gene, a candidate tumour suppressor mutated in over 70% of lung cancers), 9p (including the p16INK4a, p19ARF genes, which are involved in the RB signalling pathway), 13q (RB) and 17p (TP53).8 Loss of 3p and 9p are thought to be early events in lung cancer development, whereas loss of 17p occurs later.8 Distinct patterns of chromosomal imbalances, including duplications and loss of heterozygosity, have been observed in adenocarcinomas from both smokers and non-smokers.9, 10 ---------------------------------------------------------------------------------------- So many questions - a scare in the family. Awaiting test results. J |