Abstract
Introduction/Background
Published studies on association of germline monogenic genes and lung cancer risk
were inconsistent. Our objective is to assess the validity of reported candidate monogenic
genes for their association with lung cancer.
Materials and Methods
A systematic review of published papers prior to August 2022 was performed first to
identify all genes where germline mutations were associated with lung cancer risk.
We then performed a confirmation study in 2,050 lung cancer cases and 198,553 controls
in the UK Biobank (UKB). Germline mutations of these genes were identified from sequencing
data and annotated using The American College of Medical Genetics criteria. The robust
SKAT-O, a gene-based analysis that properly controls for false positives due to unbalanced
case-control ratio, was used for association tests adjusting for age at recruitment,
gender, and genetic background.
Results
The systematic review identified 12 genes that were statistically significantly associated
with lung cancer risk in at least one study (P < .05), including ATM, BLM, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, MSH6, PMS1, RAD51C, RAD51D, and TP53. When pathogenic/likely pathogenic mutations were aggregated within each gene, the
association was confirmed for ATM (P = 4.47E-4) at the study-wise significance level (P < .0042, Bonferroni correction for 12 tests). Suggestive evidence of association
was found for 2 other genes, BRCA2 (P = .007) and TP53 (P = .03). Among these 3 genes, the lung cancer risks range from 1.95 (BRCA2) to 5.28 (TP53).
Conclusion
This study provides statistical evidence for association of previously reported genes
and lung cancer risk and has clinical utility for risk assessment and genetic counseling.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Lung CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Lung Cancer 2020: Epidemiology, Etiology, and Prevention.Clin Chest Med. 2020; 41: 1-24https://doi.org/10.1016/j.ccm.2019.10.001
- Cancer statistics, 2022.CA Cancer J Clin. 2022; 72: 7-33https://doi.org/10.3322/caac.21708
- Cancer progress and priorities: lung cancer.Cancer Epidemiol Biomarkers Prev. 2019; 28: 1563-1579https://doi.org/10.1158/1055-9965.EPI-19-0221
- Delays in the diagnosis of lung cancer.J Thorac Dis. 2011; 3: 183-188https://doi.org/10.3978/j.issn.2072-1439.2011.01.01
- Lung Cancer in Non-Smokers.Mo Med. 2020; 117: 375-379
- Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment.Mayo Clin Proc. 2019; 94: 1623-1640https://doi.org/10.1016/j.mayocp.2019.01.013
- Reduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409https://doi.org/10.1056/NEJMoa1102873
- Screening for lung cancer: US preventive services task force recommendation statement.JAMA. 2021; 325: 962-970https://doi.org/10.1001/jama.2021.1117
- Lung cancer, genetic predisposition and smoking: the Nordic twin study of cancer.Thorax. 2017; 72: 1021-1027https://doi.org/10.1136/thoraxjnl-2015-207921
- Familial risk and heritability of cancer among twins in Nordic countries.JAMA. 2016; 315: 68-76https://doi.org/10.1001/jama.2015.17703
- Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium.Eur J Cancer. 2012; 48: 1957-1968https://doi.org/10.1016/j.ejca.2012.01.038
- Systematic review of the relationship between family history and lung cancer risk.Br J Cancer. 2005; 93: 825-833https://doi.org/10.1038/sj.bjc.6602769
- Association between family history of lung cancer and lung cancer risk: a systematic review and meta-analysis.Lung Cancer. 2020; 148: 129-137https://doi.org/10.1016/j.lungcan.2020.08.012
- Clinical and genomic features of Chinese lung cancer patients with germline mutations.Nat Commun. 2022; 13: 1268https://doi.org/10.1038/s41467-022-28840-5
- Inherited rare, deleterious variants in ATM Increase lung adenocarcinoma risk.J Thorac Oncol. 2020; 15: 1871-1879https://doi.org/10.1016/j.jtho.2020.08.017
- The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility.Transl Lung Cancer Res. 2020; 9: 646-658https://doi.org/10.21037/tlcr-19-403
- The UK Biobank resource with deep phenotyping and genomic data.Nature. 2018; 562: 203-209https://doi.org/10.1038/s41586-018-0579-z
- ClinGen variant curation expert panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation.Hum Mutat. 2018; 39: 1614-1622https://doi.org/10.1002/humu.23645
- UK biobank whole-exome sequence binary phenome analysis with robust region-based rare-variant test.Am J Hum Genet. 2020; 106: 3-12https://doi.org/10.1016/j.ajhg.2019.11.012
- Protein-altering germline mutations implicate novel genes related to lung cancer development.Nat Commun. 2020; 11: 2220https://doi.org/10.1038/s41467-020-15905-6
- Association of BRCA2 K3326* with small cell lung cancer and squamous cell cancer of the skin.J Natl Cancer Inst. 2018; 110: 967-974https://doi.org/10.1093/jnci/djy002
- Targeting mutations in cancer.J Clin Invest. 2022; 132https://doi.org/10.1172/JCI154943
- Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the college of American pathologists, the international association for the study of lung cancer, and the association for molecular pathology.J Mol Diagn. 2018; 20: 129-159https://doi.org/10.1016/j.jmoldx.2017.11.004
- Revisiting Li-Fraumeni syndrome from TP53 mutation carriers.J Clin Oncol. 2015; 33: 2345-2352https://doi.org/10.1200/JCO.2014.59.5728
- Breast cancer risk genes - association analysis in more than 113,000 women.N Engl J Med. 2021; 384: 428-439https://doi.org/10.1056/NEJMoa1913948
- Review of the lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.Clin Genet. 2009; 76: 1-18https://doi.org/10.1111/j.1399-0004.2009.01230.x
- Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer.JAMA. 2018; 319: 2401-2409https://doi.org/10.1001/jama.2018.6228
- Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.Prostate. 2021; 81: 1002-1008https://doi.org/10.1002/pros.24195
- Rare, pathogenic germline variants in fanconi anemia genes increase risk for squamous lung cancer.Clin Cancer Res. 2019; 25: 1517-1525https://doi.org/10.1158/1078-0432.CCR-18-2660
- Patterns and functional implications of rare germline variants across 12 cancer types.Nat Commun. 2015; 6: 10086https://doi.org/10.1038/ncomms10086
- Pathogenic germline variants in 10,389 adult cancers.Cell. 2018; 173 (e314): 355-370https://doi.org/10.1016/j.cell.2018.03.039
- Association of pathogenic variants in hereditary cancer genes with multiple diseases.JAMA Oncol. 2022; 8: 835-844https://doi.org/10.1001/jamaoncol.2022.0373
Mandola AB, Reid B, Sirror R, et al. Ataxia telangiectasia diagnosed on newborn screening-case cohort of 5 years' experience. Front Immunol 2019; 10:2940. doi:10.3389/fimmu.2019.02940
- Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.Br J Cancer. 2011; 105: 586-591https://doi.org/10.1038/bjc.2011.266
- Modeling ATM mutant proteins from missense changes confirms retained kinase activity.Hum Mutat. 2009; 30: 1222-1230https://doi.org/10.1002/humu.21034
- Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.Am J Hum Genet. 2009; 85: 427-446https://doi.org/10.1016/j.ajhg.2009.08.018
- Prioritizing variants in complete hereditary breast and ovarian cancer genes in patients lacking known BRCA mutations.Hum Mutat. 2016; 37: 640-652https://doi.org/10.1002/humu.22972
- Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.Int J Cancer. 2019; 144: 1962-1974https://doi.org/10.1002/ijc.31921
- Screening for germline EGFR T790M mutations through lung cancer genotyping.J Thorac Oncol. 2012; 7: 1049-1052https://doi.org/10.1097/JTO.0b013e318250ed9d
- Germline mutation of T790M and dual/multiple EGFR mutations in patients with lung adenocarcinoma.Clin Lung Cancer. 2016; 17: e5-11https://doi.org/10.1016/j.cllc.2015.11.003
- Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award.JAMA. 2014; 312: 1091-1092https://doi.org/10.1001/jama.2014.12483
- Performance of three inherited risk measures for predicting prostate cancer incidence and mortality: a population-based prospective analysis.Eur Urol. 2020; 79: 419-426https://doi.org/10.1016/j.eururo.2020.11.014
Article info
Publication history
Published online: January 25, 2023
Accepted:
January 19,
2023
Received in revised form:
January 9,
2023
Received:
September 7,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
