Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk

Li, Yafang; Xiao, Xiangjun; Lǐ, Jiànróng; Byun, Jinyoung; Cheng, Chao; Bossé, Yohan; McKay, James; Albanes, Demetrios; Lam, Stephen; Tardón, Adonina; Chu, Chen; Bojesen, Stig E.; Landi, Maria Teresa; Johansson, Mattias; Risch, Angela; Bickeböller, Heike; Wichmann, H‐Erich; Christiani, David C.; Rennert, Gad; Arnold, Susanne M.; Goodman, Gary E.; Field, John K.; Davies, Michael; Shete, Sanjay; Marchand, Loı̈c Le; Melander, Olle; Brunnström, Hans; Liu, Geoffrey; Hung, Rayjean J.; Andrew, Angeline S.; Kiemeney, Lambertus A.; Shen, Hongbing; Sun, Ryan; Zienolddiny, Shan; Grankvist, Kjell; Johansson, Mikael; Caporaso, Neil E.; Teare, Dawn; Hong, Yun-Chul; Lazarus, Philip; Schabath, Matthew B.; Aldrich, Melinda C.; Schwartz, Ann G.; Gorlov, Ivan P.; Purrington, Kristen; Yang, Ping; Liu, Yanhong; Han, Younghun; Bailey-Wilson, Joan E.; Pinney, Susan M.; Mandal, Diptasri; Willey, James C.; Gaba, Colette; Brennan, Paul; Amos, Christopher I.

doi:10.1093/hmg/ddac030

Cited by 3 publications

(2 citation statements)

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“…Endogenous factors that potentially contribute to sex differences in age at diagnosis among lung cancer in patients who never smoke include the distribution of lung cancer histological subtypes, tumor mutations and genetic susceptibility [44,45,[56][57][58][59]. For example, females are at an increased risk compared to males of developing lung cancer with a driver mutation, such as the epidermal growth factor receptor (EGFR) [60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity

Blechter,

Wong,

Chien

et al. 2024

Br J Cancer

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Background We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. Methods We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student’s t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. Results We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = −2.2 (95% confidence interval (CI):−2.5, −1.9), in Shanghai (n = 1049) (Δ years = −1.6 (95% CI:-2.9, −0.3), and in Sutter Health and Kaiser Permanente Hawaiʽi in the US (n = 82) (Δ years = −11.3 (95% CI: −17.7, −4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. Conclusions We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

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Section: Discussionmentioning

confidence: 99%

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity

Blechter,

Wong,

Chien

et al. 2024

Br J Cancer

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“…The main risk factor for developing NSCLC is smoking, which is preventable yet highly prevalent with over a billion smokers around the world [ 2 ]. Moreover, smoking and other environmental pollutants interact with biological factors such as aging and genetic risk variants to increase disease burden [ 3 , 4 , 5 , 6 ]. Furthermore, the NSCLC risk has been shown to correlate positively with the severity and duration of smoking and negatively with the time since smoking cessation [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer

et al. 2022

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Lung cancers are the leading cause of cancer-related deaths worldwide. Studies have shown that non-small cell lung cancer (NSCLC), which constitutes the majority of lung cancers, is significantly more responsive to early-stage interventions. However, the early stages are often asymptomatic, and current diagnostic methods are limited in their precision and safety. The cell-free RNAs (cfRNAs) circulating in plasma (liquid biopsies) offer a non-invasive detection of spatial and temporal changes occurring in primary tumors since the early stages. To address gaps in the current cfRNA knowledge base, we conducted a pilot study for the comprehensive analysis of transcriptome-wide changes in plasma cfRNA in NSCLC patients. Total cfRNA was extracted from archived plasma collected from NSCLC patients (N = 12), cancer-free former smokers (N = 12), and non-smoking healthy volunteers (N = 12). Plasma cfRNA expression levels were quantified by using a tagmentation-based library preparation and sequencing. The comparisons of cfRNA expression levels between patients and the two control groups revealed a total of 2357 differentially expressed cfRNAs enriched in 123 pathways. Of these, 251 transcripts were previously reported in primary NSCLCs. A small subset of genes (N = 5) was validated in an independent sample (N = 50) using qRT-PCR. Our study provides a framework for developing blood-based assays for the early detection of NSCLC and warrants further validation.

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CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity

Nygård,

Valta,

Laine

et al. 2023

Front. Genet.

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Enteroviral infections have been linked to the development of islet autoimmunity (IA) and type 1 diabetes (T1D), and the coxsackie and adenovirus receptor (CXADR) is one of the ligands used by adenoviruses and enteroviruses for cell internalization. Two CXADR single nucleotide polymorphisms (SNPs), rs6517774 and rs2824404, were previously associated with an increased susceptibility to IA in the international TEDDY study (The Environmental Determinants of Diabetes in the Young). This study aimed to replicate the results by genotyping 2886 children enrolled in the Finnish Diabetes Prediction and Prevention study (DIPP). In our preliminary analysis of the SNPs’ allelic distributions, we could not find any association with IA susceptibility. However, a stratified analysis revealed a sex disparity, since the allelic distribution of rs6517774 was different when comparing autoantibody positive females with males; a difference not seen in healthy subjects. By using HLA risk groups and sex as covariates, a Cox regression survival analysis found that the rs6517774 (A/G) SNP was associated with a lower age at seroconversion in females (Female*rs6517774-AA; HR = 1.53, p = 0.002), while introducing a protective effect in males. Accordingly, we propose that rs6517774 alters IA characteristics by modifying the age at seroconversion in a sex-dependent manner. In light of this observation, rs6517774 now joins a limited set on SNPs found to introduce sex-dependent risk effects on the age at IA initiation.

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Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk

Cited by 3 publications

References 46 publications

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity

A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer

CXADR polymorphism rs6517774 modifies islet autoimmunity characteristics and exhibits sex disparity

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