Association between KITLG Gene Polymorphisms and Testicular Germ Cell Tumors: A Systematic Review and Meta-analysis

Background Acute lymphoid leukaemia (ALL) is the commonest childhood cancer whose incidence is rising in many nations. In the USA, between 1975 and 2016, ALL rates (ALLRs) rose 93.51% from 1.91 to 3.70/100,000 < 20 years. ALL is more common in Caucasian-Americans than amongst minorities. The cause of both the rise and the ethnic differential is unclear, however, prenatal cannabis exposure was previously linked with elevated childhood leukaemia rates. We investigated epidemiologically if cannabis use impacted nationally on ALLRs, its ethnic effects, and if the relationship was causal. Methods State data on overall, and ethnic ALLR from the Surveillance Epidemiology and End Results databank of the Centre for Disease Control (CDC) and National Cancer Institute (NCI) were combined with drug (cigarettes, alcoholism, cannabis, analgesics, cocaine) use data from the National Survey of Drug Use and Health; 74.1% response rate. Income and ethnicity data was from the US Census bureau. Cannabinoid concentration was from the Drug Enforcement Agency Data. Data was analyzed in R by robust and spatiotemporal regression. Results In bivariate analyses a dose-response relationship was demonstrated between ALLR and Alcohol Use Disorder (AUD), cocaine and cannabis exposure, with the effect of cannabis being strongest (β-estimate = 3.33(95%C.I. 1.97, 4.68), P = 1.92 × 10− 6). A strong effect of cannabis use quintile on ALLR was noted (Chi.Sq. = 613.79, P = 3.04 × 10− 70). In inverse probability weighted robust regression adjusted for other substances, income and ethnicity, cannabis was independently significant (β-estimate = 4.75(0.48, 9.02), P = 0.0389). In a spatiotemporal model adjusted for all drugs, income, and ethnicity, cannabigerol exposure was significant (β-estimate = 0.26(0.01, 0.52), P = 0.0444), an effect increased by spatial lagging (THC: β-estimate = 0.47(0.12, 0.82), P = 0.0083). After missing data imputation ethnic cannabis exposure was significant (β-estimate = 0.64(0.55, 0.72), P = 3.1 × 10− 40). 33/35 minimum e-Values ranged from 1.25 to 3.94 × 1036 indicative of a causal relationship. Relaxation of cannabis legal paradigms had higher ALLR (Chi.Squ.Trend = 775.12, P = 2.14 × 10− 112). Cannabis legal states had higher ALLR (2.395 ± 0.039 v. 2.127 ± 0.008 / 100,000, P = 5.05 × 10− 10). Conclusions Data show that ALLR is associated with cannabis consumption across space-time, is associated with the cannabinoids, THC, cannabigerol, cannabinol, cannabichromene, and cannabidiol, contributes to ethnic differentials, demonstrates prominent quintile effects, satisfies criteria for causality and is exacerbated by cannabis legalization.

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“…Other loci have since been described including rs995030 and this is an area of active research enquiry at this time [ 138 ].…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

Reece

Hulse

2021

BMC Cancer

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“…Other similar loci have also been described including rs995030 and research in this area is on-going at the present time [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly the nature of the different genetic risk between African-Americans and Caucasian-Americans has been precisely defined as being due to a differing allelic frequency at an anomalous P53 response element on Chromosome 9 which drives cellular proliferation rather than the usual suppression of growth-related activities in cells experiencing genotoxic stress which is more generally associated with P53 activation [ 7 , 8 ]. This effect is described further in the Discussion.…”

Section: Introductionmentioning

confidence: 99%

Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence

Reece

Hulse

2021

BMC Pharmacol Toxicol

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Background Ethnic differences in testicular cancer rates (TCRs) are recognized internationally. Cannabis is a known risk factor for testicular cancer (TC) in multiple studies with dose-response effects demonstrated, however the interaction between ancestral and environmental mutagenic effects has not been characterized. We examined the effects of this presumed gene-environment interaction across US states. Methods State based TCR was downloaded from the Surveillance Epidemiology and End Results (SEER) website via SEERStat. Drug use data for cigarettes, alcohol use disorder, analgesics, cannabis and cocaine was taken from the National Survey of Drug Use and Health a nationally representative study conducted annually by the Substance Abuse and Mental Health Services Administration (SAMHSA) with a 74.1% response rate. Cannabinoid concentrations derived from Drug Enforcement Agency publications. Median household income and ethnicity data (Caucasian-American, African-American, Hispanic-American, Asian-American, American-Indian-Alaska-Native-American, Native-Hawaiian-Pacific-Islander-American) was from the US Census Bureau. Data were processed in R using instrumental regression, causal inference and multiple imputation. Results 1975–2017 TCR rose 41% in African-Americans and 78.1% in Caucasian-Americans; 2003–2017 TCR rose 36.1% in Hispanic-Americans and 102.9% in Asian-Pacific-Islander-Americans. Ethnicity-based scatterplot-time and boxplots for cannabis use and TCR closely mirrored each other. At inverse probability-weighted interactive robust regression including drugs, income and ethnicity, ethnic THC exposure was the most significant factor and was independently significant (β-estimate = 4.72 (2.04, 7.41), P = 0.0018). In a similar model THC, and cannabigerol were also significant (both β-estimate = 13.87 (6.33, 21.41), P = 0.0017). In additive instrumental models the interaction of ethnic THC exposure with Asian-American, Hispanic-American, and Native-Hawaiian-Pacific-Islander-American ethnicities was significant (β-estimate = − 0.63 (− 0.74, − 0.52), P = 3.6 × 10− 29, β-estimate = − 0.25 (− 0.32, − 0.18), P = 4.2 × 10− 13, β-estimate = − 0.19 (− 0.25, − 0.13), P = 3.4 × 10− 9). After multiple imputation, ethnic THC exposure became more significant (β-estimate = 0.68 (0.62, 0.74), P = 1.80 × 10− 92). 25/33 e-Values > 1.25 ranging up to 1.07 × 105. Liberalization of cannabis laws was linked with higher TCR’s in Caucasian-Americans (β-estimate = 0.09 (0.06, 0.12), P = 6.5 × 10− 10) and African-Americans (β-estimate = 0.22 (0.12, 0.32), P = 4.4 × 10− 5) and when dichotomized to illegal v. others (t = 6.195, P = 1.18 × 10− 9 and t = 4.50, P = 3.33 × 10− 5). Conclusion Cannabis is shown to be a TC risk factor for all ethnicities including Caucasian-American and African-American ancestries, albeit at different rates. For both ancestries cannabis legalization elevated TCR. Dose-response and causal relationships are demonstrated.

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Overexpression of KITLG predicts unfavorable clinical outcomes and promotes lymph node metastasis via the JAK/STAT pathway in nasopharyngeal carcinoma

Ling

Zhang

Chang

et al. 2022

Laboratory Investigation

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Association between KITLG Gene Polymorphisms and Testicular Germ Cell Tumors: A Systematic Review and Meta-analysis

Cited by 5 publications

References 16 publications

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

Cannabinoid exposure as a major driver of pediatric acute lymphoid Leukaemia rates across the USA: combined geospatial, multiple imputation and causal inference study

Causal inference multiple imputation investigation of the impact of cannabinoids and other substances on ethnic differentials in US testicular cancer incidence

Overexpression of KITLG predicts unfavorable clinical outcomes and promotes lymph node metastasis via the JAK/STAT pathway in nasopharyngeal carcinoma

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