Genetic Prediction of Smoking Cessation Medication Side Effects: A Genome-Wide Investigation of Abnormal Dreams on Varenicline.

Varenicline, the most efficacious smoking cessation monotherapy, produces abnormal dreams. Although genetic contributions to varenicline-associated nausea and cessation have been identified, the role of genetics in abnormal dreams is unknown. We conducted a genomewide association study (GWAS) of abnormal dreams in 188 European ancestry smokers treated with varenicline (NCT01314001). Additive genetic models examined the likelihood of experiencing abnormal dreams 2 weeks following varenicline initiation. For the top locus, we tested for selectivity to varenicline, effects on cessation, replication, and generalizability to African ancestry (AA) individuals. The top GWAS variant associated with abnormal dreams was rs901886, mapping to intron 2 of ICAM5 on chromosome 19. The prevalence of abnormal dreams in those with rs901886 CC, CT, and TT genotypes was 15%, 36%, and 62%, respectively (odds ratio = 2.94 for T vs. C, 95% confidence interval = 1.92-4.55, P = 2.03e-7; T allele frequency = 52%). This rs901886 association was selective to varenicline (P values > 0.05 on nicotine patch and placebo). There were also positive associations for rs901886 T (vs. C allele, P = 0.03) and for abnormal dreams (P = 0.06) with varenicline-aided cessation. Neither rs901886 (P = 0.40) nor abnormal dreams (P = 0.24) were associated with adherence. A similar direction of effect of rs901886 on abnormal dreams was observed in a second varenicline trial (NCT01836276). In AA individuals (n = 137), rs901886 was not associated with abnormal dreams (P = 0.41), but there was an association for a variant located ~ 74.4 kb 5' of ICAM5 (P = 2.56e-3). Variation in ICAM5 may influence abnormal dreams and cessation on varenicline. These findings provide additional support for genetically optimized smoking cessation approaches.

CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study.

CYP2A6, a genetically variable enzyme, inactivates nicotine, activates carcinogens, and metabolizes many pharmaceuticals. Variation in CYP2A6 influences smoking behaviors and tobacco-related disease risk. This phenome-wide association study examined associations between a reconstructed version of our weighted genetic risk score (wGRS) for CYP2A6 activity with diseases in the UK Biobank (N = 395 887). Causal effects of phenotypic CYP2A6 activity (measured as the nicotine metabolite ratio: 3'-hydroxycotinine/cotinine) on the phenome-wide significant (PWS) signals were then estimated in two-sample Mendelian Randomization using the wGRS as the instrument. Time-to-diagnosis age was compared between faster versus slower CYP2A6 metabolizers for the PWS signals in survival analyses. In the total sample, six PWS signals were identified: two lung cancers and four obstructive respiratory diseases PheCodes, where faster CYP2A6 activity was associated with greater disease risk (Ps < 1 × 10-6). A significant CYP2A6-by-smoking status interaction was found (Psinteraction < 0.05); in current smokers, the same six PWS signals were found as identified in the total group, whereas no PWS signals were found in former or never smokers. In the total sample and current smokers, CYP2A6 activity causal estimates on the six PWS signals were significant in Mendelian Randomization (Ps < 5 × 10-5). Additionally, faster CYP2A6 metabolizer status was associated with younger age of disease diagnosis for the six PWS signals (Ps < 5 × 10-4, in current smokers). These findings support a role for faster CYP2A6 activity as a causal risk factor for lung cancers and obstructive respiratory diseases among current smokers, and a younger onset of these diseases. This research utilized the UK Biobank Resource.

Brain and cortisol responses to smoking cues are linked in tobacco-smoking individuals.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Less cortical complexity in ventromedial prefrontal cortex is associated with a greater preference for risky and immediate rewards.

In our everyday lives, we are often faced with situations in which we have to make choices that involve risky or delayed rewards. However, the extent to which we are willing to accept larger risky (over smaller certain) or larger delayed (over smaller immediate) rewards vary across individuals. Here we investigated the relationship between cortical surface complexity in medial prefrontal cortex and individual differences in risky and intertemporal preferences. We found that lower cortical complexity in ventromedial prefrontal cortex (vmPFC) was associated with a greater preference for risky and immediate rewards. In addition to these common structural associations in mPFC, we also found associations between lower cortical complexity and a greater preference for immediate rewards that extended into left dorsomedial prefrontal cortex and right vmPFC. Taken together, the shared association suggests that lower cortical complexity in vmPFC may be a structural marker for individual differences in impulsive behavior.

Bayesian regularization to predict neuropsychiatric adverse events in smoking cessation with pharmacotherapy.

BACKGROUND: Research on risk factors for neuropsychiatric adverse events (NAEs) in smoking cessation with pharmacotherapy is scarce. We aimed to identify predictors and develop a prediction model for risk of NAEs in smoking cessation with medications using Bayesian regularization. METHODS: Bayesian regularization was implemented by applying two shrinkage priors, Horseshoe and Laplace, to generalized linear mixed models on data from 1203 patients treated with nicotine patch, varenicline or placebo. Two predictor models were considered to separate summary scores and item scores in the psychosocial instruments. The summary score model had 19 predictors or 26 dummy variables and the item score model 51 predictors or 58 dummy variables. A total of 18 models were investigated. RESULTS: An item score model with Horseshoe prior and 7 degrees of freedom was selected as the final model upon model comparison and assessment. At baseline, smokers reporting more abnormal dreams or nightmares had 16% greater odds of experiencing NAEs during treatment (regularized odds ratio (rOR) = 1.16, 95% credible interval (CrI) = 0.95 - 1.56, posterior probability P(rOR > 1) = 0.90) while those with more severe sleep problems had 9% greater odds (rOR = 1.09, 95% CrI = 0.95 - 1.37, P(rOR > 1) = 0.85). The prouder a person felt one week before baseline resulted in 13% smaller odds of having NAEs (rOR = 0.87, 95% CrI = 0.71 - 1.02, P(rOR < 1) = 0.94). Odds of NAEs were comparable across treatment groups. The final model did not perform well in the test set. CONCLUSIONS: Worse sleep-related symptoms reported at baseline resulted in 85%-90% probability of being more likely to experience NAEs during smoking cessation with pharmacotherapy. Treatment for sleep disturbance should be incorporated in smoking cessation program for smokers with sleep disturbance at baseline. Bayesian regularization with Horseshoe prior permits including more predictors in a regression model when there is a low number of events per variable.

Influence of CYP2A6 Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success.

INTRODUCTION: Genetic variation in Cytochrome P450 2A6 (CYP2A6), the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations. AIMS AND METHODS: Adult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n = 567) or slow (n = 432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. Fagerström test for nicotine dependence scores were measured at baseline and biochemically verified smoking cessation was assessed at end of treatment. RESULTS: Dependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n = 591 European, n = 408 African ancestry) or sex (n = 444 women, n = 555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95 to 1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e. interaction) effect ORs ranged from 0.88 to 1.61 (p = .397-.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high versus low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high versus low dependence had lower quit rates in all three treatment arms. CONCLUSIONS: Although nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers. IMPLICATIONS: Variation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

Clinical and laboratory genetic counselor attitudes on the reporting of variants of uncertain significance for multigene cancer panels.

Research suggests variants of uncertain significance (VUSs) present a variety of challenges for genetic counselors (GCs), nongenetics clinicians, and patients. Multigene cancer panels reveal more VUSs than single gene testing as a result of the increase in the number of genes being tested. This study surveyed 87 clinical cancer GCs involved with direct patient care and 19 laboratory GCs who provide guidance to clinicians regarding genetic test results about their attitudes on various options for the reporting of VUSs by laboratories for broad multigene cancer panels. Independent samples t-tests were utilized to compare the two groups. Based on a six-point Likert-type scale (1 = Strongly Disagree to 6 = Strongly Agree), clinical cancer GCs (M = 5.4; SD = 0.8) and laboratory GCs (M = 5.2; SD = 0.9) agreed overall that VUSs should be reported (p = 0.44; Cohen's d = 0.21). When asked about specific reporting options, both clinical cancer GCs (M = 1.9; SD = 1.1) and laboratory GCs (M = 2.1; SD = 1.4) disagreed that VUSs should be reported only for genes related to the indication for testing (p = 0.50; Cohen's d = 0.17). Overall, most GCs felt clinicians should not choose whether VUSs should be reported on genetic test results, with clinical cancer GCs (M = 1.9; SD = 1.3) feeling more strongly against it than laboratory GCs (M = 3.1; SD = 1.4; p = 0.002; Cohen's d = 0.88). Generally, GCs were more in favor of VUSs not being reported for population-based screening, with laboratory GCs (M = 4.7; SD = 0.8) agreeing more with that practice than clinical cancer GCs (M = 3.7; SD = 1.4; p = 0.001; Cohen's d = 0.80). Both clinical cancer GCs (M = 4.1; SD = 1.2) and laboratory GCs (M = 3.9; SD = 1.2) agreed additional guidelines on how to approach VUSs in clinical practice should be developed (p = 0.54; Cohen's d = 0.17). While most GCs supported the reporting of VUSs overall, our analyses suggest clinical cancer and laboratory GCs may have different attitudes toward specific VUS-related reporting options. Further research is needed to elucidate GC preferences to help inform best practices for the reporting of VUSs. The development of additional standardized guidelines on how to approach VUSs would further support clinical practice.

An fMRI-Based Brain Marker of Individual Differences in Delay Discounting.

Individual differences in delay discounting-how much we discount future compared to immediate rewards-are associated with general life outcomes, psychopathology, and obesity. Here, we use machine learning on fMRI activity during an intertemporal choice task to develop a functional brain marker of these individual differences in human adults. Training and cross-validating the marker in one dataset (Study 1, N = 110 male adults) resulted in a significant prediction-outcome correlation (r = 0.49), generalized to predict individual differences in a completely independent dataset (Study 2: N = 145 male and female adults, r = 0.45), and predicted discounting several weeks later. Out-of-sample responses of the functional brain marker, but not discounting behavior itself, differed significantly between overweight and lean individuals in both studies, and predicted fasting-state blood levels of insulin, c-peptide, and leptin in Study 1. Significant predictive weights of the marker were found in cingulate, insula, and frontoparietal areas, among others, suggesting an interplay among regions associated with valuation, conflict processing, and cognitive control. This new functional brain marker is a step toward a generalizable brain model of individual differences in delay discounting. Future studies can evaluate it as a potential transdiagnostic marker of altered decision-making in different clinical and developmental populations.SIGNIFICANCE STATEMENT People differ substantially in how much they prefer smaller sooner rewards or larger later rewards such as spending money now versus saving it for retirement. These individual differences are generally stable over time and have been related to differences in mental and bodily health. What is their neurobiological basis? We applied machine learning to brain-imaging data to identify a novel brain activity pattern that accurately predicts how much people prefer sooner versus later rewards, and which can be used as a new brain-based measure of intertemporal decision-making in future studies. The resulting functional brain marker also predicts overweight and metabolism-related blood markers, providing new insight into the possible links between metabolism and the cognitive and brain processes involved in intertemporal decision-making.

Willingness to Use Commercial Nicotine Gums, Lozenges, and Gummies Among Nontobacco Using Adolescents in Southern California.

PURPOSE: New oral nicotine products (ONPs), often advertised as "tobacco-free" (i.e., pouches, gum, lozenges, gummies), come in nontobacco flavors appealing to adolescents. It is unknown how adolescent willingness to use ONPs differs by product type and flavor, and whether sociodemographic disparities exist. METHODS: Adolescent never tobacco product users (n = 1, 289) in ninth or 10th grade from 11 high schools in Southern California were surveyed in fall 2021 about ever and past 6-month use of ONPs and sociodemographic characteristics. Adolescents were randomized to view five different ONPs in either fruit or mint flavor, and asked to rate their willingness to use each product. Multivariable logistic random effect-repeated measures regression examined associations of product type, flavor, and sociodemographic characteristics with any willingness to use ONPs. RESULTS: Compared to traditional smokeless tobacco (willingness = 17.8%), adolescents reported greater willingness to use ONPs (gum, 28.2%; pouches, 21.1%; lozenge, 22.4%; gummies, 24.1%); adjusted odd ratios [aORs] 1.25-1.84; p-values<.001). Mint flavor (23.3%) compared to fruit flavor (21.4%), significantly increased odds of willingness to use across all ONPs (aOR [95%CI] = 1.15 [1.05, 1.26], p = .004). Younger adolescents (ninth, 24.2% vs. 10th grade, 21.4%) and LGBTQ+ (34.2%) versus heterosexual (19.7%) and cisgender (18.8%) adolescents were more willing to use these products. DISCUSSION: Adolescents reported greater willingness to use new ONPs compared to traditional smokeless tobacco. Adolescents who were younger (vs. older adolescents) or identified as LGBTQ+ (vs. heterosexual and cisgender) were more willing to use new ONPs. Efforts to monitor adolescents' willingness to use and actual use of these products are warranted.

Young adults' beliefs about modern oral nicotine products: Implications for uptake in nonvapers, dual use with e-cigarettes, and use to reduce/quit vaping.

Modern oral nicotine products (ONPs; nontherapeutic nicotine pouches, gums, lozenges, and gummies) may be perceived in ways that could promote uptake in nonvapers, dual use with e-cigarettes, or use to quit vaping. In this cross-sectional digital remote survey of 1,460 respondents aged 21-24 from Southern California, we examined beliefs about ONPs among past-30-day e-cigarette nonusers, users unmotivated to quit vaping, and users motivated to quit vaping. Positive beliefs about ONPs were reported by 31.8% of the overall sample and higher in past-30-day e-cigarette users (with or without quit motivation) than nonusers. Perceiving ONPs to be easy to conceal, convenient, and able to be used where vaping/smoking is not allowed were the most common types of beliefs reported. Among e-cigarette users with quit motivation (n = 142), interest in using ONPs to quit/reduce vaping (44.4%) was higher than interest in using medicinal nicotine gum/lozenges (23.4%), nicotine patch (17.6%), or prescription medications (16.6%). Interest in using ONPs to reduce/quit vaping (vs. no interest) was greater among participants who reported vaping ≥ 20 (vs. < 10) days in the past month, vaping ≥ 10 (vs. < 10) times per day, low/moderate (vs. high) quit vaping self-efficacy, and low/moderate (vs. high) desire to quit vaping. These findings suggest that: (a) appreciable subsets of the young adult population may hold positive beliefs about ONPs that could promote ONP uptake, particularly e-cigarette users and (b) some young adult e-cigarette users may be interested in using ONPs to reduce/quit vaping, particularly frequent vapers with relatively lower self-efficacy and desire to quit vaping. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Integration of Universal Germline Genetic Testing for All New Breast Cancer Patients.

BACKGROUND: The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described. METHODS: A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT. RESULTS: The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM, 1 BRCA1, 3 BRCA2, 1 BRIP1, 1 CFTR, 1 CHEK2, 1 MUTYH, 1 PALB2, 1 PRSS1, 1 RAD50, 1 RET, and 2 TP53), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery. CONCLUSIONS: New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.

Development of Machine Learning Algorithms Incorporating Electronic Health Record Data, Patient-Reported Outcomes, or Both to Predict Mortality for Outpatients With Cancer.

PURPOSE: Machine learning (ML) algorithms that incorporate routinely collected patient-reported outcomes (PROs) alongside electronic health record (EHR) variables may improve prediction of short-term mortality and facilitate earlier supportive and palliative care for patients with cancer. METHODS: We trained and validated two-phase ML algorithms that incorporated standard PRO assessments alongside approximately 200 routinely collected EHR variables, among patients with medical oncology encounters at a tertiary academic oncology and a community oncology practice. RESULTS: Among 12,350 patients, 5,870 (47.5%) completed PRO assessments. Compared with EHR- and PRO-only algorithms, the EHR + PRO model improved predictive performance in both tertiary oncology (EHR + PRO v EHR v PRO: area under the curve [AUC] 0.86 [0.85-0.87] v 0.82 [0.81-0.83] v 0.74 [0.74-0.74]) and community oncology (area under the curve 0.89 [0.88-0.90] v 0.86 [0.85-0.88] v 0.77 [0.76-0.79]) practices. CONCLUSION: Routinely collected PROs contain added prognostic information not captured by an EHR-based ML mortality risk algorithm. Augmenting an EHR-based algorithm with PROs resulted in a more accurate and clinically relevant model, which can facilitate earlier and targeted supportive care for patients with cancer.

A neural signature of the vividness of prospective thought is modulated by temporal proximity during intertemporal decision making.

Why do people discount future rewards? Multiple theories in psychology argue that one reason is that future events are imagined less vividly than immediate events, thereby diminishing their perceived value. Here we provide neuroscientific evidence for this proposal. First, we construct a neural signature of the vividness of prospective thought, using an fMRI dataset where the vividness of imagined future events is orthogonal to their valence by design. Then, we apply this neural signature in two additional fMRI datasets, each using a different delay-discounting task, to show that neural measures of vividness decline as rewards are delayed farther into the future.

Differences in intention to use flavored oral nicotine products among young adult e-cigarette users and non-users.

New oral nicotine products (ONPs; nicotine pouches, gums, lozenges, and gummies), which are regulated as nonmedicinal tobacco products in the U.S., have flavors and other characteristics that previously attracted young adults to e-cigarettes. Whether young adults' interest in ONPs differs by e-cigarette use status and quit-vaping motivation is unknown but important for understanding the possible health impact of ONPs. It is particularly important to study if nonmedicinal ONPs attract e-cigarette users interested in quitting vaping, given that nicotine replacement (NRT) therapy uptake in young adults is low. In this study, ONP non-users (ages: 20-24) from California viewed digital images of 5 flavored ONPs (4 nonmedicinal and one NRT gum product) and reported intention to use each ONP (0-100 score). Main and interactive effects of Group (past-6-month e-cigarette non-users [n = 1,1388], e-cigarette users unmotivated to quit vaping [n = 168], and e-cigarette users motivated to quit vaping [n = 99]) and ONP type (nonmedicinal gum, nonmedicinal lozenge, gummy, pouch, and NRT gum) on use intention were tested. For each nonmedicinal ONP, use intention was higher in both e-cigarette user groups than non-users (ds = 0.47-0.59; Ps < 0.001), but did not differ between e-cigarette users with and without quit-vaping motivation (Ps ≥ 0.31). A Group × ONP type interaction was found, whereby higher use intention for e-cigarette users with vs without quit motivation was present for only gum NRT (Cohens d = 0.17; P =.01). Among young adults, e-cigarette users might be more inclined than e-cigarette non-users to try nonmedicinal ONPs regardless of quit-vaping motivation.

Risk-reducing mastectomy decisions among women with mutations in high- and moderate- penetrance breast cancer susceptibility genes.

BACKGROUND: Women harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high-risk screening or risk-reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making. METHODS: We performed a retrospective study assessing RRM decisions for 279 women. RESULTS: Women with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age. CONCLUSION: Although national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision-making in this population.

Leadership Diversity and Development in the Nation's Cancer Centers.

The capacity and diversity of the oncology leadership workforce has not kept pace with the emerging needs of our increasingly complex cancer centers and the spectrum of challenges our institutions face in reducing the cancer burden in diverse catchment areas. Recognizing the importance of a diverse workforce to reduce cancer inequities, the Association of American Cancer Institutes conducted a survey of its 103 cancer centers to examine diversity in leadership roles from research program leaders to cancer center directors. A total of 82 (80%) centers responded, including 64 National Cancer Institute-designated and 18 emerging centers. Among these 82 respondents, non-Hispanic White individuals comprised 79% of center directors, 82% of deputy directors, 72% of associate directors, and 72% of program leaders. Women are underrepresented in all leadership roles (ranging from 16% for center directors to 45% for associate directors). Although the limited gender, ethnic, and racial diversity of center directors and perhaps deputy directors is less surprising, the demographics of current research program leaders and associate directors exposes a substantial lack of diversity in the traditional cancer center senior leadership pipeline. Sole reliance on the cohort of current center leaders and leadership pipeline is unlikely to produce the diversity in cancer center leadership needed to facilitate the ability of those centers to address the needs of the diverse populations they serve. Informed by these data, this commentary describes some best practices to build a pipeline of emerging leaders who are representative of the diverse populations served by these institutions and who are well positioned to succeed.

Differences in Young Adults' Perceptions of and Willingness to Use Nicotine Pouches by Tobacco Use Status.

Oral nicotine pouches may appeal to young adult current nicotine/tobacco users interested in alternative forms of nicotine that lack pulmonary exposure, but may also appeal to young adult non-users of nicotine/tobacco products. We used data from a 2020 remote digital survey of an ongoing cohort study of young adults from Southern California (aged 19-23) to examine differences in pouch perceptions and use willingness across nicotine/tobacco use statuses. Participants who had never used nicotine pouches (N = 1167) viewed text/imagery from mass-marketed pouch packaging and advertising, then completed measures of willingness to use nicotine pouches, pouch harm perceptions, and hypothetical choice of cigarettes or e-cigarettes over pouches. Willingness to use pouches was significantly higher among non-combustible only (33.8%), combustible only (29.3%), and dual (43.9%) users than non-users (14.7%). Overall, 49.1% of participants were uncertain whether pouches were less harmful than cigarettes and 52.4% were uncertain whether pouches were less harmful than e-cigarettes. Relative harm perceptions did not significantly differ by tobacco use status. Those using non-combustible products (either alone or as part of dual use with combustible tobacco) had greater odds than non-users of reporting that they would use e-cigarettes over nicotine pouches. By contrast, all tobacco product user groups reported greater odds than non-users that they would use cigarettes over pouches. In sum, a sizable minority of young adults might be willing to try using nicotine pouches, but most are uncertain about the relative harm of pouches.

Examining the role of mitochondrial genetic variation in nicotine dependence.

Nicotine dependence (ND) has a heritability rate of ∼50%, suggesting genetic factors contribute to underlying mechanisms. Here, we aimed to examine variants within both mtDNA and the nuclear genome to determine if mitochondrial genes are associated with ND. A total of 129 mtDNA SNPs and 1136 nuclear-encoded mitochondrial genes in a sample of N = 374 Caucasians were selected for analysis. Age of onset of first, occasional, and daily smoking and Fagerström Test for Nicotine Dependence were used as outcomes for the analysis. Linear regression was used to test common variants. Gene analyses were performed using MAGMA. One nuclear mitochondrial SNP, rs78417112 found in the HSD17B4 gene, was significantly associated with the age of onset of occasional smoking. Additionally, one nuclear mitochondrial gene, PRKACA, was significantly associated with age of onset of both first and occasional smoking. Replication testing of the mtDNA m.1700T>C SNP, nominally associated with age of onset of daily smoking, was available in the PNAT2 clinical trial (N = 930 Caucasians). A meta-analysis showed this SNP was associated with age of onset of daily smoking (p-value = 0.004). Overall, the findings suggest mitochondrial genetic variation may contribute to variability in smoking phenotypes, although replication in larger samples is required.

Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes.

OBJECTIVES: We evaluated multiple genotyping/sequencing approaches in a homologous region of chromosome 19, and investigated associations of two common 3'-UTR CYP2A6 variants with activity in vivo. METHODS: Individuals (n = 1704) of European and African ancestry were phenotyped for the nicotine metabolite ratio (NMR), an index of CYP2A6 activity, and genotyped/sequenced using deep amplicon exon sequencing, SNP array, genotype imputation and targeted capture sequencing. Amplicon exon sequencing was the gold standard to which other methods were compared within-individual for CYP2A6, CYP2A7, CYP2A13, and CYP2B6 exons to identify highly discordant positions. Linear regression models evaluated the association of CYP2A6*1B and rs8192733 genotypes (coded additively) with logNMR. RESULTS: All approaches were ≤2.6% discordant with the gold standard; discordant calls were concentrated at few positions. Fifteen positions were discordant in >10% of individuals, with 12 appearing in regions of high identity between homologous genes (e.g. CYP2A6 and CYP2A7). For six, allele frequencies in our study and online databases were discrepant, suggesting errors in online sources. In the European-ancestry group (n = 935), CYP2A6*1B and rs8192733 were associated with logNMR (P < 0.001). A combined model found main effects of both variants on increasing logNMR. Similar trends were found in those of African ancestry (n = 506). CONCLUSION: Multiple genotyping/sequencing approaches used in this chromosome 19 region contain genotyping/sequencing errors, as do online databases. Gene-specific primers and SNP array probes must consider gene homology; short-read sequencing of related genes in a single reaction should be avoided. Using improved sequencing approaches, we characterized two gain-of-function 3'-UTR variants, including the relatively understudied rs8192733.