Table 3 summary of the included studies reporting on the potential association between FHC and germline mutations

Tefre et al Br J Cancer (1990)

Case–control study

Norway/not available

83 patients with lung cancer; 129 unmatched healthy controls

SCLC and NSCLC

Any cancer (unspecified degree and tumors among relatives)

Not available

4.8% of never smokers

FH of cancer was not associated with germline EcoR1 polymorphism of L-myc

–

Hong et al J Prev Med Public Health (2011)

Case–control study

Korea/Asian

406 patients with NSCLC; 428 unmatched controls

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 20.4% (cases)

85.2% of ever smoker

FHC was not associated with diagnosis of NSCLC

In patients without FHC, the miR-196a2 CT/TT germline genotype was associated with diagnosis of NSCLC

Xu et al PLoS One (2013)

Case–control study

China/Asian

1017 male patients with lung cancer; 1017 matched healthy controls

NSCLC, SCLC and others

Any cancer (unspecified degree and tumors among relatives)

FHC of 12.8% (cases)

14.8% of never smokers, 36.4% of former smokers 48.8% of current smokers

FHC was significantly associated with the diagnosis of lung cancer

Germline rs1564483GA, AA and GA + AA BCL2 SNPs were associated with decreased risk of lung cancer among patients with not FHC

He et al J Hum Genet (2013)

Case–control study

China/Asian

507 patients with NSCLC; 662 unmatched controls

NSCLC

Lung cancer (unspecified degree among relatives)

FH of lung cancer of 21.7% (cases)

36.9% of never smokers, 43.1% of ever smokers

FH of lung cancer was associated with the diagnosis of NSCLC (OR 1.47, 95%CI: 1.09–1.98)

FH of lung cancer was associated with the diagnosis of NSCLC even among smokers (OR 1.94, 95%CI: 1.21–3.12)

Several XRCC3 and XRCC4 germ-line SNPs were associated with the diagnosis of NSCLC

Some XRCC3 and XRCC4 haplotypes and diplotypes were associated with diagnosis of NSCLC, with synergistic effect for increased risk with FH of lung cancer

Tian et al Cell Biochem Biophys (2014)

Case–control study

China/Asian

391 patients with NSCLC; 663 matched controls

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 27.4% (cases)

25.8% of ever smokers

FHC was associated with the diagnosis of NSCLC

Significant enrichment of germline NQO1 C609T TT SNP compared to CC among cases

Germline NQO1 C609T TT SNP was associated with diagnosis of NSCLC after adjustment for FHC

Su et al Cell Physiol Biochem (2015)

Observational, retrospective

China/Asian

610 patients with NSCLC

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 17.5%

29.0% of never smokers, 23.28% of former smokers, 47.7% of current smokers

FHC was not associated with survival

Germline hOGG1 (rs1052133 C > G) SNP was associated with shorter survival among patients without FHC

The hOGG1 G allele correlated with shorter survival among patients without FHC (HR 1.60, 95%CI: 1.04—2.45)

Javid et al Clin Transl Oncol (2015)

Case–control study

India/not available

155 patients with NSCLC; 155 matched controls

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 12.2% (cases)

28.4% of never smokers, 71.6% of ever smokers

Polymorphism in the inhibitory P2

promoter region of anti-apoptotic BCL-2 genes was associated with diagnosis of NSCLC (-938CC/AC)

Patients with FHC enriched in BCL92 (-938AA) genotype

Liu et al J Thorac Oncol (2016)

Case–control study

USA/White

54 patients with familial lung cancer and 48 patients with sporadic lung cancer

NSCLC, SCLC and others

Lung cancer (in at least 3 first-degree relatives)

–

14.8% of never smokers, 85.2% of ever smokers

Patients with FH of lung cancer were younger, with higher prevalence of female and never smokers than those with sporadic lung cancer,

30 germline variants of interest found in 33.3% of patients with FH and 29.2% of patients with no FH

Patients with FH of lung cancer were not significantly enriched of deleterious mutations found in the whole study population [heterozygous c.2086C > T in the coiled-coil domain-containing 147 gene (CCD147), and two SNV p.Val26Met and p.Met563Thr, of the dopamine beta-hydroxylase gene (DBH)]

Xu et al Cancer Manag Res (2019)

Observational, retrospective

China/Asian

987 patients with NSCLC

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 20.2%

62.4% of never smokers, 37.6% of ever smokers

No association between FHC and survival

Germline rs915894 AC/CC genotype of the NOTCH4 gene was associated with decreased risk of death, with a greater effect among patients with FHC

Patients with rs915894 AA genotype of the NOTCH4 gene and positive FHC showed increased risk of death

Liu et al Transl Lung Cancer Res (2020)

Retrospective study

China/Asian

1026 patients with NSCLC

NSCLC

Lung cancer (in at least one first-degree relatives)

FH of lung cancer of 26.8%

43.1% of never smokers, 56.9% of ever smokers

Germline mutations categorized as pathogenic, likely pathogenic or non-pathogenic group

Patients with FH of lung cancer were significantly enriched in pathogenetic (57.1%) and likely pathogenetic (32.3%) mutations, compared to non-pathogenetic (26.2%) (p = 0.026)

Lancheros et al Nutrients (2022)

Case–control study

Spain/Caucasian

204 cases of NSCLC; 408 unmatched controls

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC of 49.5% (cases)

13.24% of never smokers, 39.71% of former smokers, 47.96% of current smokers

FHC was associated with diagnosis of NSCLC (OR 15.2, 95%CI: 9.55–25.2)

The Vitamin D Receptor (VDR) BsmI rs1544410-AA germline SNP was associated with lower risk of NSCLC after adjusting for FHC and smoking

Rifkin et al. Clin Lung Cancer (2023)

Case–control study

United Kingdom/Withes (94.7%)

2050 patients with lung cancer/198533 controls

Lung cancer (not specified)

Lung cancer (unspecified degree among relatives)

FH of lung cancer of 21.0%

20% of never smokers, 46.6% of former smokers, 33.4% of current smokers

FH of lung cancer was significantly associated with diagnosis of lung cancer

FH of lung cancer (whole cohort including cases and controls) was significantly associated to germline mutations in 3 significant genes (ATM, BRCA2, TP53)