Table 1 summary of the included studies reporting on the potential role of FHC as a risk factor for lung cancer

Tsugane et al Jpn J Clin Oncol (1987)

Case–control study

Japan/Asian

185 patients with lung cancer diagnosis between 30 and 49 years; 134 matched controls

NSCLC, SCLC and others

Any cancer (up to second-degree relatives)

FHC 36% and 32% for male and female patients with adenocarcinoma respectively FH of lung cancer of 6% and 2% for male and female patients with adenocarcinoma respectively

FHC of 30% and FH of lung cancer of 5% among patients with squamous cell carcinoma

Adenocarcinoma histology: 75% male patients were ever smokers,15% of female patients were ever smokers

 > 90% of patients with other tumors were ever smokers

FHC was not associated with diagnosis of early onset lung cancer

–

Osann

Cancer Res (1991)

Case–control study

USA (86%

White, 11% black, and 3% Asian)

217 females diagnosed with lung cancer; 217 matched controls

NSCLC, SCLC and others

Any cancer categorized as smoking related and smoking unrelated tumors (first-degree relatives)

FHC of 22.6% and 45.2% among never and ever smokers. FH of lung cancer of 3.2% and 9.0% among never and ever smokers

84.8% of ever smokers

FHC was significantly associated with diagnosis of lung cancer (OR 1.8, 95% CI 1.0–3.2)

Stronger association in women aged ≤ 55 (OR 3.8, 95% CI 0.9– 16.2) than those aged > 55 years (OR 1.4, 95% CI 0.7–2.6)

Smoking and FHC showed synergistic effect in increasing risk of lung cancer

Gorlova et al Int J Cancer (2006)

Case–control study

USA/White (82.5%), Hispanic (8.9%), Black (8.6%)

280 cases of lung cancer in never/light smokers (< 100 cigarettes in lifetime); 242 unmatched healthy controls

NSCLC, SCLC and others

Any cancer, any smoking-related cancer (lung, head and neck, kidney, bladder and pancreatic), lung cancer, lung cancer in at least 1 never-smoker relative, any cancer detected before 50 years

FHC of 68.9%, FH of smoking-related cancer of 20.8%, FH of lung cancer of 13.2%, FH of lung cancer in at least one never smokers of 2.3%; FH of any cancer among relatives aged < 50 years 31.5%

All cases were never smokers (< 100 cigarettes in lifetime)

No significant association between overall FHC, FH of smoking-related cancers, and FH of lung cancer, and diagnosis of lung cancer

FH of any caner among relatives aged < 50 years was associated with the diagnosis of lung cancer (OR 1.87, 95% CI 1.13–3.1)

Chen et al Cancer (2007)

Case–control study

Taiwan/Asian

826 female patients with lung cancer and 531 unmatched heathy controls

NSCLC, SCLC and others

Breast, ovarian, cervical, and endometrial cancers (first-degree relatives)

FHC (breast, ovarian, cervical and endometrial) 7.7%

7.1% of ever smokers 69.5% of patients were exposed to passive smoking

No difference in FHC between cases and controls

Association between Hormone Replacement Therapy (HRT) and reduced risk of lung cancer among patients with negative FHC (OR 0.69, 95% CI 0.51–0.95)

Schwartz et al J Clin Oncol (2007)

Case–control study

USA/White (77%), Black (23%)

488 women with NSCLC; 498 matched controls

NSCLC

Lung cancer (first-degree relatives)

FH of lung cancer of 25%

8% of never smokers, 32% of former smokers, 60% of current smokers

FH of lung cancer was significantly associated with diagnosis of NSCLC (p < 0.001)

–

Tammemagi et al Cancer Epidemiol Biomarkers Prev (2007)

Observational, retrospective Case-case study

Canada/White (87.5%), Black (4.2%), Hispanic (2.1%), Asian (6.3%)

48 cases with Small Aggressive NSCLC (SA-NSCLC) and 329 controls enrolled in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

NSCLC

Lung cancer (first-degree relatives)

FH of lung cancer of 26.1%

10.4% of never smokers, 52.1% of former smokers, 37.5% of current smokers

FH of lung cancer was not associated with diagnosis of SA-NSCLC

In patients with FH of lung cancer diagnosis of SA-NSCLC was significantly more frequent among females

Cassidy et al Eur J Cancer (2009)

Case–control study

Europe/not available

733 surgically resected patients; 1312 matched controls

NSCLC

Any cancer, lung cancer, smoking-related cancers, and gastric cancer (first-degree relatives)

FH of any cancer 51.5%, FH of lung cancer 18.9%

7.1% of never smokers, 75.4% of former smokers, 17.5% of current smokers

FH for any cancer significantly associated with diagnosis of risk of NSCLC (OR 1.16, 95%: 1.02–1.33)

FH of lung cancer, FH of smoking-related cancers, and FH of non-smoking related cancers not associated with diagnosis of NSCLC

Significant association between FH of gastric cancer and diagnosis of NSCLC, between FH of gastric cancer and late-onset NSCLC (≥ 55 years), and between

FH of lung cancer and diagnosis of early-onset NSCLC (< 55 years)

Cote et al Carcinogenesis (2009)

Case–control study

USA/White (48.9%), Black (48.7%)

504 female patients with NSCLC; 527 matched controls

NSCLC

Lung cancer (first-degree relatives)

FH of lung cancer of 25.8%

7.9% of never smokers, 31.6% of former-smokers, 60.5% of current smokers

FH of lung cancer associated with diagnosis of NSCLC in both white and black patients (p < 0.01)

FH of lung cancer was among the factors in the most parsimonious model able to predict risk of NSCLC in white ever-smoker women together with age at diagnosis, history of chronic obstructive lung disease, pack-years of cigarette smoking, BMI, XRCC1 A/A genotypes, GSTM1 null and COMT A/G or G/G phenotype

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

Schwartz et al Carcinogenesis (2011)

Case–control study

USA/Black (African-Americans)

837 cases with lung cancer; 975 matched controls

NSCLC, SCLC and others

Lung cancer (unspecified degree among relatives)

FH of lung cancer of 22%

8.2% of never smokers, 91.8% of ever smokers

FH of lung cancer was significantly associated with diagnosis of lung cancer (p < 0.001)

Excess European ancestry on chromosome 1 at rs6587361 for NSCLC. Excess African ancestry on chromosome 3 at rs181696 among ever smokers with NSCLC

Sin et al J Clin Oncol (2013)

Retrospective study with exploratory and validation cohorts

Canada/White (97.6%), Asian (0.9%), Black (0.6%)

2,485 patients from the Pan-Can Study 61 Cases and 122 matched controls from the CARET study

NSCLC

Lung cancer (unspecified degree among relatives)

FH of lung cancer 5.37%

All patients reported a history of smoking

FH and risk of lung cancer were not associated with diagnosis of NSCLC in the Pan-Can cohort

Pro–Surfactant Protein B (SFTPB—log transformed) associated with diagnosis of lung cancer

No association between FH of lung cancer and SFTPB

Xu et al PLoS One (2013)

Case–control study

China/Asian

1017 male patients with lung cancer; 1017 matched healthy controls 242 cases assessed for clinical outcomes

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

Yilmaz et al Asian Pac J Cancer Prev (2014)

Case–control study

Turkey/not available

100 patients with lung cancer; 100 matched healthy controls

NSCLC, SCLC and others

Any cancer (unspecified degree and tumors among relatives)

FHC of 23%

90% of smokers

FHC was significantly associated with diagnosis of lung cancer diagnosis (p = 0.001)

No association between MTHFR C677T polymorphism and diagnosis of lung cancer

Pathak et al J Cancer Ther Res (2014)

Case–control study

USA/White (83%), Black (17%)

453 female patients with NSCLC; 478 matched controls

NSCLC

Lung cancer (unspecified degree and tumors among relatives)

FH of lung cancer of 24% among white participants and 28.7% among Black participants

90.3% and 91.5% of ever smokers among White and African American, respectively

FH of lung cancer was associated with diagnosis of lung cancer in both whites and Black participants (p < 0.01)

Germline single nucleotide polymorphisms (SNP) APAF-1 rs1007573 and CD40 rs1535045 were associated with lung cancer in white participants, while SNP TP63 rs6790167 was associated with lung cancer in black participants

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

Li et al Int J Clin Exp Med (2016)

Case–control study

China/Asian

420 patients with lung cancer aged ≤ 45 years; 1673 matched controls

NSCLC, SCLC and others (cases)

Lung cancer (first-, second-degree relatives and collateral relatives)

FH of lung cancer of 7.3%

27.6% of never smokers, 72.4% of ever smokers

FH of lung cancer was associated with diagnosis of lung cancer risk (p = 0.03)

FH of lung cancer among first- and second-degree relatives more strongly associated with diagnosis of lung cancer than FH of lung cancer among collateral relatives

White and Horvitz (2017)

Case–control study, exploratory

USA/not available

5443 web-identified potential cases and remaining 4,813,985 web users as controls

Likely diagnosis of lung cancer

Lung cancer (unspecified degree among relatives)

NA

NA

FHC associated with likely diagnosis of lung cancer (RR 7.548, 95% CI 3.9–14.4)

–

Tammemagi et al Lancet Oncol (2017)

Prospective, single arm study

Canada/White (97%), Black (3%)

164 patients with lung cancer among 2537 ever-smoker enrolled subjects between 50 and 75 years without history of cancer at enrollment

NSCLC, SCLC and others

Lung cancer (first-degree relatives)

FH of lung cancer 39%

All patients reported a history of smoking

No significant association between FH of lung cancer and diagnosis of lung cancer within the study population

-

Warkentin et al JNCI Cancer Spectr (2018)

Observational, retrospective. Case-case study

USA/White (96.9%)

64 patients with SA-NSCLC and 206 non-SA-NSCLC cases enrolled in the National Cancer Institute’s National Lung Screening Trial

NSCLC

Lung cancer (first-degree relatives)

FH of lung cancer 31.8%

All patients reported a history of smoking

FH of lung cancer was not associated with diagnosis of SA-NSCLC

FH of lung cancer associated with SA-NSCLC among female patients

Brown et al Cancer Epidemiol Biomarkers Prev (2019)

Case–control study

USA/White (93.5%), Black (5.3%)

262 cases with lung cancer; 528 matched controls

NSCLC

Lung cancer (unspecified degree among relatives)

FH of lung cancer 22.9%

All patients reported a history of smoking

No significant association between FH of lung cancer and diagnosis of lung cancer within the study population

–

Titan et al J Thorac Cardiovasc Surg (2020)

Observational, retrospective

USA/ White (88.6%)

75,587 female patients aged from 50 to 74 years enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)

1147 patients with NSCLC

Any cancer and Lung cancer (unspecified degree and tumors among relatives)

FHC of 59.4% and FH of lung cancer of 11.4% (whole study cohort)

NA

FH of lung cancer was associated with the risk of developing NSCLC over time (HR 1.79, 95%CI: 1.56–2.06)

FH of lung cancer is associated with the risk of developing NSCLC independently of hormone replacement therapy

Jin et al Int J Cancer (2021)

Case–control study

Japan, China, USA, Singapore, Malaysia and others/Asian

Pooled analysis of the International Lung Cancer Consortium (ILCCO) including 264 women with lung cancer and 5342 matched controls

NSCLC, SCLC and others

Lung cancer (first-degree relatives)

FH of lung cancer 6.2%

65.3% of never smokers, 10.5% of former smokers, 23.7% of current smokers

FH of lung cancer was significantly associated with diagnosis of lung cancer (p < 0.01)

–

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

Albano et al Cancer Epidemiol (2023)

Observational, retrospective

USA/not available

16,056 never smoker patients with 579 cases of lung cancer

Lung cancer (not specified)

Lung cancer (unspecified degree among relatives)

FH of lung cancer 28.7%

NA

FH of lung cancer was associated with diagnosis of lung cancer (OR 1.87, 95% CI 1.55–2–26)

–

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)

Liu et al Nutrients (2023)

Observational, retrospective

China/Asian

1283 patients with NSCLC and 215 patients with benign lung nodules

NSCLC

Any cancer (unspecified degree and tumors among relatives)

FHC 20.7%

62.9% of never smokers, 14.2% of former-smokers, 22.9% of current smokers

FHC was not associated with diagnosis of NSCLC

FHC was associated with diagnosis of intrapulmonary metastasis among patients with NSCLC at univariable analysis