Table 3 Top five hits from discovery and validation association analysis.

From: Rare deleterious germline variants and risk of lung cancer

Candidates

n. (freq.%) carriers

   

Meta-analysis&

  

(ClinVar)

TRICL: 1045 LC, 885 Control

GELCC: 380 LC, COPDGene: 318 Control

TCGA: 1015 LC, GnomAD: 134,187 Control

GWAS studies @ OncoArray/Affymetrix

Total freq.% carrier LC/Control

OR (95% CI)

P-value

ATM missense SNV p.V2716A, rs587782652 (Pathogenic)

2 (0.19%) / 0

0 / 0

2 (0.20%)/ 5 (0.004%)

5 (0.03%) / 0 @ OncoArray

0.05% / 0.003%

19.55 (5.04–75.6)

1.7e-05

POMC 3′ UTR deletion c.*28delT, rs756770132 (VUS)

6 (0.57%) / 0

4 (1.05%) 1 FLC / 0

6 (0.59%) / 207 (0.17%)

-

0.66% / 0.15%

4.33 (2.03–9.24)

0.00015

STAU2 LoF deletion p.N364M fs*67, rs746501298

21 (2.01%) / 4 (0.45%)

4 (1.05%) 3 FLC / 0

0 / 25 (0.02%)

-

1.02% / 0.02%

4.48 (1.73–11.55)

0.0019

MPZL2 LoF deletion p.I24M fs*22, rs752672077 (Pathogenic)

3 (0.29%) / 0

4 (1.05%) 2 FLC / 0

5 (0.49%) / 189 (0.15%)

-

0.49% / 0.14%

3.88 (1.71–8.8)

0.0012

MLNR LoF deletion, p.Q334V fs*3, rs563947699

9 (0.86%) 3 FHLC/ 0

6 (1.58%) 2 FLC / 0

7 (0.69%) / 431 (0.35%)

29 (0.54%) / 49 (0.86%) @ Affymetrix

0.65% / 0.34%

2.69 (1.33–5.43)

0.0060

  1. TRICL Transdisciplinary Research in Cancer of the Lung, SNV single nucleotide variants, Indels insertion (ins)/deletion (del), LoF loss of function, fs frameshift, VUS variant of uncertain significance from ClinVar, NA not available, LC lung cancer, AD adenocarcinoma, FLC familiar lung cancer, OR odds ratio, CI confidence interval.
  2. #The validation sets include 26,803 LCs and 555,107 controls: 1) Genetic Epidemiology of LC (GELCC) WES data for 380 LCs (122 FLC and 258 sporadic); 2) COPDGene WES data for 318 controls; 3) TCGA (The Cancer Genome Atlas) WES data for 1015 LCs; 4) GnomAD (genome aggregation database) WES and WGS data for 134,187 non-cancer controls; 5) OncoArray genotyping data for 17,878 LCs vs. 13,425 controls; 6) Affymetrix exome array data for 5364 LCs vs. 5724 controls; 7) UK Biobank (UKB) genotyping data for 2166 LCs vs. 401,453 controls.
  3. @The ATM p.V2716A genotype was from the OncoArray study; the MLNR p.Q334V deletion genotype was from the Affymetrix study.
  4. &The freq.% of carriers were based on the available cases and controls. False discovery rate (FDR) adjusted P-values indicate significant associations based on a fixed-effect meta-analysis.
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