Evidence for a genetical contribution to non-smoking-related lung cancer

Abstract

Non-smoking-related lung cancer cases show significant excess relatedness for close and distant relationships, providing strong evidence for a genetical contribution as well as an environmental contribution. Significant excess relatedness for only close family relationships in all lung cancer cases and in only smoking-related lung cancer cases implies environmental contribution. Additionally, the highest RR for lung cancer was observed in the relatives of smoking-related lung cancer, suggesting predisposition gene carriers who smoke are at highest risk for lung cancer. Screening and gene identification should focus on high-risk pedigrees.

Lung cancer, genetic predisposition and smoking: the Nordic Twin Study of Cancer

“…In contrast to D398N, associations with other loci found to be significant for lung cancer such as those in 5p15 (TERT and CLPTM1L genes) and 6p21 (BAG6/BAT3) are found also in non-smokers 6 32. The existence of a modest familial liability to lung cancer independent of smoking status was also observed in the analysis of Utah genealogical data 41. An increased risk of lung cancer was seen even in distant relatives; the high proportion of non-smoking lung cancer cases (31%) and a large proportion of missing data on smoking status (which was assessed through the death certificate and not prospectively) calls for replication in other populations.…”

Familial clustering of oropharyngeal squamous cell carcinoma in the Utah population

“…Utah's population is reflective of its founding Mormon pioneers, which consisted of largely unrelated groups of northern Europeans from Scotland, Wales, Denmark, Sweden, and England. Subsequent migration over the ensuing years along with a more recent substantial influx of international migrants contributes to a population mix that is thought to be representative of the broader United States and northern European countries . However, our requirement of significant genealogy data for each case and control to allow genetic analysis limited the population we analyzed to original Utah pioneer pedigrees, which are exclusively of Northern European ancestry.…”

“…Subsequent migration over the ensuing years along with a more recent substantial influx of international migrants contributes to a population mix that is thought to be representative of the broader United States and northern European countries. 29 However, our requirement of significant genealogy data for each case and control to allow genetic analysis limited the population we analyzed to original Utah pioneer pedigrees, which are exclusively of Northern European ancestry. It should be recognized that extrapolations to other populations should not be made without additional evaluation.…”

Age-related late-onset disease heritability patterns and implications for genome-wide association studies

“…It is perhaps for this reason that the Nordic twin studies consortium, which was invaluable in the three other cancer analyses, primarily restricted itself to analyzing the effects of tobacco smoking on LC . Factors such as asbestos, industrial smoke and pollutants, high levels of domestic radon in some areas of the world, or exposure of miners to radon or other sources of radiation may influence incidence and, if not accounted for, may affect heritability estimates (Krewski et al, 2005;Carr et al, 2015;Malhotra et al, 2016). Hereditary mutations of genes that regulate DNA repair, including BRCA1/2, TP53 and others, also increase the risk of LC, as with almost any cancer (Kanwal et al, 2017).…”

“…The mostly polygenic fraction of lung cancer heritability is hypothesized to be similarly stable with age, as is the case with the other three cancers reviewed. (Ford et al, 1998;Antoniou et al, 2003;Risch et al, 2006;Mavaddat et al, 2010;Haley, 2016;Michailidou et al, 2017) (Hjelmborg et al, 2014;Wu and Gu, 2016;Mancuso et al, 2016;Walsh, 2017;Lecarpentier et al, 2017;Eeles et al, 2017) (Jiao et al, 2014;Schmit et al, 2016;de Voer et al, 2016;) (Krewski et al, 2005;Weissfeld et al, 2015;Carr et al, 2015;Malhotra et al, 2016;Kanwal et al, 2017;Shi et al, 2017; Lifetime risk numbers, when marked, "w" for women, "m" for men. Lifetime risk numbers, when marked, "w" for women, "m" for men.…”