A DRD1 Polymorphism Predisposes to Lung Cancer among Those Exposed to Secondhand Smoke during Childhood

Abstract

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6 and DRD1 were mined for single nucleotide polymorphisms (SNPs) that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3’UTR SNP in DRD1 (Dopamine Receptor D1) was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood (OR: 0.69; 0.60, 0.79; P<0.0001). This relationship was evident in both ever (OR: 0.74; 0.62, 0.88; P=0.001) and never smokers (OR 0.61; 0.47, 0.79; P<0.0001), European American (OR: 0.65; 0.53, 0.80; P<0.0001) and African American (OR: 0.73; 0.62, 0.88; P=0.001) populations. While much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between a SNP in the 3’UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood.

Relationship between anti-depressant use and lung cancer survival

“…(22,23) Recent studies have provided mechanistic evidence for a link between these neurotransmitters and cancer. (32-34) An agnostic screen of drugs that target cancer stem cells identified thioridazine(35-38)—an anti-psychotic drug that antagonizes dopamine receptors (specifically the DRD2 class)—as a potential anti-tumor drug that antagonizes VEGFR2/PI3K/mTOR signaling. (35-38) In addition, a recent compound library screen of the NCI-60 cell line repository identified the anti-psychotic trifluoperzine (TFP)—a DRD2 antagonist—as a potential anti-metastatic cancer drug.…”

Differential eligibility of African American and European American lung cancer cases using LDCT screening guidelines

“…Patients with non-small cell lung cancer were enrolled from 1998 onwards, as previously described 9. Exclusion criteria for eligibility included; being more than 24 months after initial diagnosis, non-US resident, non-English-speaking, residing in an institution such as a prison, nursing home or shelter, unable to give informed consent, diagnosis of HIV, hepatitis B or C. All cases of lung cancer were confirmed by pathological examination to determine histological subtype and stage.…”

cAMP levels in lymphocytes and CD4+ regulatory T‐cell functions are affected by dopamine receptor gene polymorphisms

“…Results raise the issue of possible relationships between DRD1 genetic variants and Treg cell dysfunction‐related disease. Interestingly, DRD1 genetic variants have been associated with cancer, but it is unclear whether Treg cells contribute . More investigations are needed in cancer as well as in autoimmunity, organ transplantation and infectious disease, because increasing the knowledge about the role of DR genetic variants in the modulation of T lymphocyte function and in particular of Treg cells might result in better understanding of individual variability of immune responses in health and disease, providing the basis for the development of tailored therapeutic approaches.…”