Christopher I. Amos, Ph.D. from the Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine speaks about Rare deleterious germline variants and risk of lung cancer.
Abstract:
Recent research suggests that rare variants have larger effect sizes and may play a key role in lung cancer etiology (LC). In the discovery package, 1045 LC cases and 885 controls were given whole-exome sequencing as well as targeted germline DNA sequencing. We based on rare and predicted deleterious variants and small indels enriched in cases or controls to uncover the inherited causal variants. In a sequence of 26,803 LCs and 555,107 monitors, promising candidates were further validated. During the discovery process, we discovered 25 unusual deleterious variants linked to LC susceptibility, including 13 that had previously been documented in ClinVar. We discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (OR 19.55, 95 percent CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95 percent CI 1.71–8.8), and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95 percent CI 2.03–9.24), STAU Endogenous DNA damage assays further supported the possible cancer-promoting function of selected candidate genes and variants. Our research culminated in the discovery of new unusual deleterious variants linked to LC susceptibility. To assess the pathogenic effects of these particular alleles, more in-depth mechanistic studies are needed.
Introduction:
Lung cancer (LC), the leading cause of cancer death in the United States, has recently seen significant reductions in mortality, owing to lower smoking rates and advances in modern therapies such as immunotherapy1. Previous genome-wide association studies (GWAS) have discovered new genetic factors that affect LC risk, which is also influenced by smoking behavior2. A missense p.D398N and a 22-bp deletion (del) in the core promoter region of CHRNA5 that affect function and expression have been found in the 15q25.1 region that shows the most important and reliable genetic signal3,4. Smoking cessation is more difficult for carriers of these variants than for noncarriers5, and they may benefit from a tailored smoking cessation intervention6.
The heritability of LC has been calculated to be 18 percent in previous studies.
7. Recent genetic studies indicate that functionally deleterious rare variants (MAF 1%) have much larger effect sizes than common variants8,9,10 since they show signs of greater selective pressure11,12, which may account for lost heritability not explained by common variants11. Fewer than 3% of protein-coding single nucleotide variants (SNVs), or around 300 genes per genome, are expected to cause loss of protein function (LoF) due to stop-gain, frameshift, or splice site disruption13. Though they are the second most common cause of human genetic variation, insertions (ins) and deletions (indels) have received little attention. Selected indels, such as the p.E746 A750del in EGFR14,15,16, have been described as being important in the development of LC.
Recent identifications of many uncommon missense variants that have a moderate-to-large impact on LC risk, such as PARK2 p.R275W (OR 5.24)17, BRCA2 p.K3326X (OR 2.47), CHEK2 p.I157T (OR 0.38)18, LTB p.L87F (OR 7.52), P3H2 p.Q185H (OR 5.39)19, DBH p.V26 (OR 8.82)
twenty-first. Finding uncommon variants in population-based studies may be difficult due to higher evolutionary pressure and poor linkage disequilibrium (LD) with common SNPs used in GWAS22. We used whole-exome sequencing (WES) and targeted sequencing on healthy controls and selected high-risk LC cases enriched with the highest genetic risk of LC, such as early-onset or family history of LC (FHLC)7,23,24, to optimize the potential for detecting large-effect, uncommon deleterious variants (SNVs and small indels 21 bp).
The following are the outcomes:
Research participants’ demographics
The validation sets (26,803 LCs and 555,107 controls) and the discovery study (Transdisciplinary Research in Cancer of the Lung (TRICL; 1,045 LCs vs. 885 controls) were mainly of European ancestry. LC cases were slightly more likely than controls to be smokers and have more pack-years (P-value 0.0001). FHLC was found to be more prevalent in the TRICL and Genetic Epidemiology of LC Consortium (GELCC) cases.