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

Abstract

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.

Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003–2017: part 3 – spatiotemporal, multivariable and causal inferential pathfinding and exploratory analyses of prostate and ovarian cancers

“…This view is closely concordant with a recent report describing cannabis exposure as a primary driver of USA pediatric cancers [ 100 ] and of the commonest cancer of childhood acute lymphoid leukaemia [ 28 ]. From the very clear findings with testicular cancer it would appear that the usual course of oncogenesis may be greatly accelerated [ 101 ].…”

“…Mathematical modelling of the relationship between increasing percentiles of cannabidiol exposure and prostate and ovarian cancer demonstrated strong evidence of a supra-linear sigmoidal relationship between rising cannabidiol exposure and cancer incidence such that increases in community cannabidiol exposure can be predicted to greatly and disproportionately increase tumour incidence. The implication of both prostate and ovary (and also testicular in [ 3 , 8 , 10 , 66 , 101 , 148 , 196 , 197 ]) cancers in this oncogenic portrait carries very grave implications for community transmission of mutagenic and oncogenic genotoxicity from both parental germ lines to subsequent generations. Further work to investigate these themes in more detail and increased depth and by groups working in related laboratory fields and epidemiological and statistical methodology is strongly indicated.…”

“…However several lines of evidence suggest that they are likely to be implicated. Several recent studies implicate many cannabinoids in genotoxic activities [ 27 , 28 , 45 , 100 , 101 , 156 , 157 , 190 – 192 ]. Long ago the genotoxic action was found to reside in the polycyclic olevitol nucleus of the cannabinoids with little modulation by the various side chains [ 29 , 190 ].…”

Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003–2017: part 1 – continuous bivariate analysis

“…This view is closely concordant with a recent report describing cannabis exposure as a primary driver of USA pediatric cancers [ 55 ] and of the commonest cancer of childhood acute lymphoid leukaemia [ 53 ]. From the very clear findings with testicular cancer it would appear that the usual course of oncogenesis in some stem cell niches may be greatly accelerated [ 51 ].…”

“…Since cannabis exposure in adolescent and young adult life is known to increase the incidence of testicular cancer [ 8 – 11 , 49 , 50 ] by an average of 2.59-fold (95%C.I. 1.60–4.19) in meta-analysis [ 50 ] it follows that cannabis exposure dramatically accelerates testicular carcinogenesis by 2.4-fold from 34 to around 12 years [ 51 ]. The molecular pathogenesis of testicular carcinogenic transformation involves key oncogenic steps including whole genome reduplication, loss of arms of dozens of chromosomes, widespread genome demethylation and functional or structural reduplication events on chromosome 12.…”