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PDF file, 102K, Linkage locations suggested by Loki on chromosome 17 by batches of 100K iterations and over all 500K iterations.

PDF file, 212K, Genome-wide multipoint model-based linkage under the three trait locus segregation models. Multipoint LOD scores have been truncated at -3. Some scores are below -3, such as for the whole of chromosome 15.

Increasing rates of human papillomavirus (HPV)–driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk.Significance:Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

Supplementary Tables 1-4, 9-16. Supplemental Table 1. Association results of SNPs with SCCHN risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 2. Association results of SNPs with oral cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 3. Association results of SNPs with oropharynx cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 4. Association results of SNPs with hypopharynx and larynx cancer risk with P-value {less than or equal to} 1x10-3 in the discovery dataset or with P-value {less than or equal to} 5x10-8 in the meta-analysis. Supplemental Table 9. Association results of previously reported SNPs in the discovery dataset. Supplemental Table 10. Association results of HLA variants with overal SCCHN cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 11. Association results of HLA variants with oral cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 12. Association results of HLA variants with oropharyngeal cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 13. Association results of HLA variants with hypo-pharyngeal and laryngeal cancer risk with P-value {less than or equal to} 0.05 in the MDACC data. Supplemental Table 14. Associations of DRB1*1301-DQA1*0103-DQB1*0603 haplotype with the risks of SCCHN and subtyp tumors. Supplementary Table 15. Correlations between standardized polygenic risk score (PRS) and the risk of oropharyngeal cancer risk in the MDACC study and OncoArray study. Supplementary table 16. Function prediction for SNPs with validated P {less than or equal to} 0.05 and meta-analysis P-value {less than or equal to} 5x10-8 with Haploreg 4.1.

PDF file, 302K, Scatter plot of the visits at possible linked QTL locations on chromosome 17 vs. iteration.

PDF file, 133K, Additional methods describing the segregation-linkage analysis approach with variable age at onset.

To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which, 434,839 typed and 7,423,250 imputed SNPs were used as the discovery. SNPs with P < 1 × 10−3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from databases of Genotypes and Phenotypes. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96 × 10−9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54 × 10−9 for the leading SNP rs142021700) was identified for hypopharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and expression quantitative trait loci analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of human leukocyte antigen loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN.Significance:Two novel risk loci for SCCHN in non-Hispanic white individuals highlight the importance of immunologic mechanism in the disease etiology.

PDF file, 89K, L-scores for three prior settings, after discarding the beginning 5K iterations

PDF file, 34K, Typical assumptions in model-based vs. model-free multipoint linkage analysis.

In precancerous and cancerous lesions, excessive growth signals resulting from activation of oncogenes or loss of tumor suppressor genes lead to intensive replication stress, which is recognized by a high level of replication-associated DNA double-strand breaks (DSB). However, the molecular mechanism by which cells alleviate excessive replication stress remains unclear. In this study, we report that the human nuclease/helicase DNA2 facilitates homologous recombination to repair replication-associated DNA DSBs, thereby providing cells with survival advantages under conditions of replication stress. The nuclease activity of DNA2 was required for DSB end resection, which allowed subsequent recruitment of RPA and RAD51 to repair DSBs and restart replication. More importantly, DNA2 expression was significantly increased in human cancers and its expression correlated with patient outcome. Our findings therefore indicate that enhanced activity of DSB resection likely constitutes one mechanism whereby precancerous and cancerous cells might alleviate replication stress. Cancer Res; 72(11); 2802–13. ©2012 AACR.

PDF file - 633K, Supplementary Fig 1: DNA2 associates with replication forks and prevents the accumulation of replication-associated DSBs. S. Fig 2: DNA2 facilitates HR repair. S. Fig 3: DNA2's function in HR repair is dependent on its nuclease activity. S. Fig 4: Biological effects of DNA2 depletion on cancer cells. S. Fig 5: Effects of DNA2 depletion on the generation of ROS. PLUS supplemental Materials and Methods

Introduction: Sharing genetic test results with different stakeholders such as family members, healthcare providers and genetic counselors (HCP/GCs), spouses/partners, and friends is a health behavior of clinical importance in genomic medicine. Methods: Using nationally representative population-based data collected from the Health Information National Trends Survey (HINTS 5, cycle 4), we identified the prevalence and factors associated with genetic test result-sharing behavior for high-risk cancer tests, genetic health risk tests, and ancestry tests within four groups: HCP/GCs, first-degree relatives (FDRs), spouse/partner, and friend/other. Results: Overall, 68.4% of those who underwent high-risk cancer genetic testing shared their results with FDRs, whereas 89.9% shared with HCP/GCs. In adjusted multivariable analyses, women were nine times more likely than men to share (p = 0.006), and those with a personal history of cancer were less likely to share with HCP/GCs (OR = 0.025, p ≤ 0.001). Of those tested for genetic health risk, 66.5% shared with HCP/GCs, 38.7% with FDRs, 66.6% with a spouse/partner, 12.8% with a friend, and 14.1% did not share results with anyone. Of those who underwent ancestry testing, very few shared results with HCP/GCs (2.6%), whereas modest sharing was reported with FDRs, spouses/partners, and friends. Discussion: These data add empirical evidence about the population prevalence of genetic information sharing and serve as a metric for public engagement with genetic testing.

Increasing rates of human papillomavirus (HPV)–driven oropharyngeal cancer (OPC) have largely offset declines in tobacco-associated head and neck squamous cell carcinoma (HNSCC) at non-OPC sites. Host immunity is an important modulator of HPV infection, persistence, and clearance, and also of immune evasion in both virally- and nonvirally-driven cancers. However, the association between collective known cancer-related immune gene variants and HNSCC susceptibility has not been fully characterized. Here, we conducted a genetic association study in the multiethnic Veterans Affairs Million Veteran Program cohort, evaluating 16,050 variants in 1,576 immune genes in 4,012 HNSCC cases (OPC = 1,823; non-OPC = 2,189) and 16,048 matched controls. Significant polymorphisms were further examined in a non-Hispanic white (NHW) validation cohort (OPC = 1,206; non-OPC = 955; controls = 4,507). For overall HNSCC susceptibility in NHWs, we discovered and validated a novel 9q31.1 SMC2 association and replicated the known 6p21.32 HLA-DQ-DR association. Six loci/genes for overall HNSCC susceptibility were selectively enriched in African-Americans (6p21.32 HLA-G, 9q21.33 GAS1, 11q12.2 CD6, 11q23.2 NCAM1/CD56, 17p13.1 CD68, 18q22.2 SOCS6); all 6 genes function in antigen-presenting regulation and T-cell activation. Two additional loci (10q26 DMBT1, 15q22.2 TPM1) were uncovered for non-OPC susceptibility, and three loci (11q24 CRTAM, 16q21 CDH5, 18q12.1 CDH2) were identified for HPV-positive OPC susceptibility. This study underscores the role of immune gene variants in modulating susceptibility for both HPV-driven and non-HPV-driven HNSCC. Additional large studies, particularly in racially diverse populations, are needed to further validate the associations and to help elucidate other potential immune factors and mechanisms that may underlie HNSCC risk. Significance: Several inherited variations in immune system genes are significantly associated with susceptibility to head and neck cancer, which could help improve personalized cancer risk estimates.

ImportanceAlthough Africa has the highest burden of cervical cancer in the world, educational resources to achieve the 90-70-90 targets set by the World Health Organization in its strategy to eliminate cervical cancer are lacking in the region.ObjectivesTo adapt, implement, and evaluate the Project Extension for Community Health Care Outcomes (ECHO), an innovative learning tool, to build capacity of clinicians to better incorporate new evidence-based guidelines into cervical cancer control policies and clinical practices.Design, Setting, and ParticipantsThis cross-sectional study assessed knowledge and practices of clinicians and support staff regarding cervical cancer prevention and control and compared them among respondents who had attended Project ECHO sessions (prior ECHO attendees) with those who had not but were planning on attending in the near future (newcomers) as part of the Cameroon Cervical Cancer Prevention Project ECHO. Satisfaction of prior ECHO attendees was also evaluated. Data were analyzed from January to March 2022.Main Outcomes and MeasuresMain outcomes were practices and knowledge regarding cervical cancer education and prevention and preinvasive management procedures compared among prior ECHO attendees and newcomers.ResultsOf the 75 participants (mean [SD] age, 36.4 [10.0] years; 65.7% [95% CI, 54.3%-77.1%] women) enrolled in this study, 41 (54.7%; 95% CI, 43.1%-66.2%) were prior ECHO attendees, and most were clinicians (55 respondents [78.6%; 95% CI, 68.7%-88.4%]). Overall, 50% (95% CI, 37.8%-62.2%) of respondents reported performing cervical cancer screening with visual inspection of the cervix after application of acetic acid (VIA) and/or visual inspection of the cervix after application of Lugol’s iodine (VILI), 46.3% (95% CI, 34.0%-58.5%) of respondents reported performing human papillomavirus (HPV) testing, and 30.3% (95% CI, 18.9%-41.7%) of respondents reported performing cervical cytological examination in their practices, Approximately one-fourth of respondents reported performing cryotherapy (25.4% [95% CI, 14.7%-36.1%]), thermal ablation (27.3% [95% CI, 16.2%-38.3%]) or loop electrosurgical excisional procedure (LEEP, 25.0% [95% CI, 14.4%-35.6%]) for treatment of preinvasive disease. The clinical use of many of these screening and treatment tools was significantly higher among prior ECHO attendees compared with newcomers (VIA/VILI: 63.2% [95% CI, 47.4%-78.9%] vs 33.3% [95% CI, 16.0%-50.6%]; P = .03; cryotherapy: 40.5% [95% CI, 24.3%-56.8%] vs 6.7% [95% CI, 0.0%-15.8%]; P = .002; thermal ablation: 43.2% [95% CI, 26.9%-59.6%] vs 6.9% [95% CI, 0.0%-16.4%]; P = .002). Knowledge about cervical cancer education, prevention, and management procedures was satisfactory in 36.1% (95% CI, 23.7%-48.5%) of respondents; this proportion was significantly higher among prior ECHO attendees (53.8% [95% CI, 37.7%-69.9%]) compared with newcomers (4.5% [95% CI, 0.0%-13.5%]; P Conclusions and RelevanceThese findings suggest that the Project ECHO e-learning and telementoring program was associated with improved skills for clinicians and support staff and enhanced quality of care for patients. In the COVID-19 era and beyond, reinforced efforts to strengthen cervical cancer knowledge and best practices through distance learning and collaboration are needed.

The 2012 report of the President’s Cancer Panel highlighted the overriding contribution of missed clinical opportunities to suboptimal HPV vaccination coverage. Since then, it remains unknown whether the rates of provider recommendations for the HPV vaccine in the US population have increased. We conducted an analysis of four rounds of the Health Information National Trends Survey (HINTS), a household survey of civilian US residents aged 18 y or older. A total of 1,415 (2012), 1,476 (2014), 1,208 (2017), and 1,344 (2018) respondents to the HINTS survey who were either HPV vaccine-eligible or living with HPV vaccine-eligible individuals were included. Overall, the rates of providers’ recommendations remained stagnated from 2012 to 2018 in all categories of the study population, except for non-Hispanic Blacks (NHBs), where this prevalence increased during the study period (AAPC = 16.4%, p

The BRAF kinase plays a critical role in the MAPK signaling pathway and is mutated in ~8% of all human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), which is found in >70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because nearly all patients progress, due to either primary or acquired resistance. A bifunctional degradation activating compound (or BiDACTM degrader) may address the liabilities of approved drugs by overcoming, or preventing the emergence of, resistance to BRAF inhibitors. Here we describe CFT1946, an orally bioavailable cereblon-based BiDAC degrader of BRAF V600 mutant proteins, and provide an overview of the medicinal chemistry path leading to its discovery. CFT1946 degrades BRAF V600 mutant proteins, while maintaining exquisite selectivity against the proteome, sparing wild type BRAF (BRAF-WT), ARAF, and CRAF. In A375 cells, CFT1946 potently degraded BRAF V600E and inhibited ERK phosphorylation and cell growth while having no effect in the mutant KRAS, BRAF-WT driven cell line HCT116. In the A375 xenograft model, oral delivery of CFT1946 at 10 mg/kg PO BID resulted in deeper and more durable tumor regression compared to a clinically relevant dose of encorafenib. Further evaluation of CFT1946 in an engineered, clinically relevant BRAFi-resistant A375 cell line (endogenous BRAF V600E + engineered expression of NRAS Q61K) demonstrated that CFT1946 both degraded BRAF V600E and caused a loss of viability in these cells, while treatment with encorafenib had no effect. In xenografts derived from this BRAFi-resistant cell line, oral dosing of CFT1946 as a single agent led to tumor growth inhibition, while treatment with a clinically relevant dose of encorafenib had no effect on tumor growth. Furthermore, dosing CFT1946 in combination with the MEK inhibitor, trametinib, resulted in significant tumor regression, whereas combining encorafenib with the same dose of trametinib had no effect. The medicinal chemistry campaign resulting in CFT1946 focused on the improvement of in vivo pharmacokinetics and rational linker design to achieve high oral bioavailability in a beyond Rule of 5 heterobifunctional degrader. The preclinical data presented herein support the planned Phase 1/2 clinical trial of CFT1946 for the treatment of BRAF-V600 mutant solid tumors. Citation Format: Yanke Liang, Mathew E. Sowa, Katrina L. Jackson, Jeffrey R. Simard, Bridget Kreger, Ping Li, Laura Poling, Joelle Baddour, Andrew Good, Hongwei Huang, Scott Eron, Christopher G. Nasveschuk, Robert Yu, Mark Fitzgerald, Victoria Garza, Morgan W. O’Shea, Gesine Veits, Jeremy Y. Yap, Moses Moustakim, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe S. Patel, Richard Deibler, Kyle S. Cole, David Cocozziello, Fazlur Rahman, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Roy M. Pollock, Stewart L. Fisher. The discovery and characterization of CFT1946: A potent, selective, and orally bioavailable degrader of mutant BRAF for the treatment of BRAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3425.

Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs. We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p

Programs aimed at boosting human papillomavirus (HPV)-related awareness are considered one of the most effective strategies for increasing vaccination uptake and eliminating HPV-associated cancers. Several US states have made strong commitments to this effort through legislation and dedicated funds. However, it is not known if these efforts have resulted in population-level increments in HPV awareness overtime. Using the Health Information National Trends Survey data, we examined the awareness of HPV and HPV vaccine in the US, between 2008 and 2018. Prevalence estimates and confidence intervals were calculated for HPV and HPV vaccine awareness. Further, we assessed awareness after stratifying by key sociodemographic characteristics. Overall, the awareness of HPV and HPV vaccine declined over time. The lowest awareness was among racial minorities, rural residents, male respondents, those aged 65 years and older, as well as those with the lowest educational and socioeconomic standing. Between 2013 and 2018, the awareness of HPV and HPV vaccine declined by almost 10% among males, those with a high school level of education or lower, and those who earned less than USD 35,000 per annum. In 2018, the awareness of HPV and HPV vaccine was highest among non-Hispanic whites (65.8% and 66.5%) and female adults (70.5% and 71.4%); however, these figures represented declines of about 5% from rates observed in 2008. Amidst a background of sub-optimal HPV vaccination uptake and a growing incidence of HPV-associated cancers in the US, HPV-related awareness within the general US population has declined over time. This calls for stricter enforcement of legislation aimed at boosting HPV awareness, as well as frequent evaluation of government-funded HPV awareness programs.

This cross-sectional study examines the association between US adults’ self-reported political ideology and support of or opposition to policies that limit visibility and restrict advertisement of tobacco products.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10–7; 5p13.2–p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10–6; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10–6; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10–5; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10–5; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10–5. Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10–5). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

BACKGROUND Infants with more severe brachial plexus birth injury (BPBI) benefit from primary nerve surgery to improve function. The timing of the surgery, however, is controversial. The Treatment and Outcomes of Brachial Plexus Injury (TOBI) study is a multicenter prospective study with the primary aim of determining the optimal timing of this surgical intervention. This study compared outcomes evaluated 18 to 36 months after "early" microsurgery (at 6 months of age). METHODS Of 216 patients who had undergone microsurgery, 118 were eligible for inclusion because they had had a nerve graft and/or transfer followed by at least 1 physical examination during the 18 to 36-month interval after the microsurgery but before any secondary surgery. Patients were grouped according to whether the surgery had been performed before or after 6 months of age. Postoperative outcomes were measured using the total Active Movement Scale (AMS) score as well as the change in the AMS score. To address hand reinnervation, we calculated a hand function subscore from the AMS hand items and repeated the analysis only for the subjects with a Narakas grade of 3 or 4. Our hypothesis was that microsurgery done before 6 months of age would lead to better clinical outcomes than microsurgery performed after 6 months of age. RESULTS Eighty subjects (68%) had early surgery (at a mean age of 4.2 months), and 38 (32%) had late surgery (at a mean age of 10.7 months and a maximum age of 22.0 months). Infants who underwent early surgery presented earlier in life, had more severe injuries at baseline, and had a significantly lower postoperative AMS scores in the unadjusted analysis. However, when we controlled for the severity of the injury, the difference in the AMS scores between the early and late surgery groups was not significant. Similarly, when we restricted our multivariable analysis to patients with a Narakas grade-3 or 4 injury, there was no significant difference in the postoperative AMS hand subscore between the early and late groups. CONCLUSIONS This study suggests that surgery earlier in infancy (at a mean age of 4.2 months) does not lead to better postoperative outcomes of BPBI nerve surgery than when the surgery is performed later in infancy (mean age of 10.7 months). LEVEL OF EVIDENCE Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background: Cancer beliefs and perceptions of cancer risk affect the cancer continuum. Identifying underlying factors associated with these beliefs and perceptions in Texas can help inform and target prevention efforts. Methods: We developed a cancer-focused questionnaire and administered it online to a nonprobability sample of the Texas population. Weighted multivariable logistic regression analysis identified key factors associated with perceptions and beliefs about cancer. Results: The study population comprised 2,034 respondents (median age, 44.4 years) of diverse ethnicity: 45.5% were non-Hispanic white, 10.6% non-Hispanic black, and 35.7% Hispanic. Self-reported depression was significantly associated with cancer risk perceptions and cancer beliefs. Those indicating frequent and infrequent depression versus no depression were more likely to believe that: (i) compared to other people their age, they were more likely to get cancer in their lifetime [OR, 2.92; 95% confidence interval (CI), 1.95–4.39 and OR, 1.79; 95% CI, 1.17–2.74, respectively]; and (ii) when they think about cancer, they automatically think about death (OR, 2.05; 95% CI, 1.56–2.69 and OR, 1.46; 95% CI, 1.11–1.92, respectively). Frequent depression versus no depression was also associated with agreement that (i) it seems like everything causes cancer (OR, 1.67; 95% CI, 1.26–2.22) and (ii) there is not much one can do to lower one's chance of getting cancer (OR, 1.44; 95% CI, 1.09–1.89). Other predictors for perceived cancer risk and/or cancer beliefs were sex, age, ethnicity/race, being born in the United States, marital status, income, body mass index, and smoking. Conclusions: Depression and other predictors are associated with cancer risk perceptions and beliefs in Texas. Impact: Increased attention to reducing depression may improve cancer risk perceptions and beliefs.

This paper compares real earnings management (REM) between Chinese family firms and U.S. family firms after the financial crisis of 2008. For the U.S. sample, there is greater REM in family firms than non-family firms, and in the post-financial crisis period than the pre-financial crisis period. For the Chinese sample, there is greater REM in family firms than non-family firms, but REM is lower in Chinese family firms relative to non-family firms in the post-financial crisis period than the pre-financial crisis period. These findings indicate that REM activities differ between U.S. and Chinese family firms in crisis and non-crisis periods.

PURPOSE: The increasing incidence of skin cancer is a global health issue. In order to identify at-risk populations in Texas, we compared sun protection behaviors and sunburn history across rural and urban counties. METHODS: An online health screening survey collected data from a non-probability sample of Texas residents in 2018. Data were weighted by sex, age, race, and ethnicity. Multinomial multivariable logistic regression identified key factors associated with sun protection behaviors and sunscreen use. Weighted Pearson’s χtest identified differences between urban and rural respondents in strength of sunscreen used and sunburn history. FINDINGS: Rural residents in Texas were less likely to seek shade (OR = 0.58; P = .004) and less likely to use sunscreen lotion (OR = 0.65; P = .013) compared to their urban counterparts. Sunscreen use was also lower among current versus never smokers (OR = 0.67; P = .034) but higher in those with personal versus no cancer history (OR = 2.14; P = .004). Although rural versus urban residents were more likely to use higher SPF sunscreen (P < .001), they had more sunburns in the past 12 months (P < .001). They also had more blistering sunburns over the course of their life (P < .001) and these injuries were more likely to occur at an earlier age, between 5–14 years old (P < .001). CONCLUSIONS: Increased attention to sun protective behaviors among rural communities in Texas is vital to help reduce the high prevalence of sunburn injury and incidence of skin cancer.

Background: HPV vaccination is highly effective at preventing several squamous cell carcinomas. However, the uptake of this vaccine remains sub-optimal in the US, with further exacerbation of this poor uptake during the pandemic. This study aims to describe changes and barriers to HPV vaccination during the COVID-19 pandemic as observed by healthcare professionals (HCPs) in the state of Texas. Methods: Data for this study were derived from a statewide cross-sectional survey of HCPs in the state of Texas (n=1283). Survey instruments were developed at MD Anderson Cancer Center, and reviewed by its IRB. Survey frequencies were used to estimate for the proportional distribution of changes as observed by HCPs regarding HPV vaccination i) uptake ii) hesitancy and iii) refusal during the COVID-19 pandemic. HCPs who observed increases in vaccination hesitancy or refusal, were then asked for the reasons cited by their patients. Survey frequencies were then used to determine the proportional distribution of the reasons cited for HPV vaccination hesitancy and refusal during the pandemic. All statistical analysis were conducted using R version 3.5.2. Results: Overall, 730 HCPs responded to the study questions of interest. A predominant proportion of respondents were employed in group practice settings or university teaching/affiliated hospitals. About 20% of HCPs in Texas observed decreases in HPV vaccination uptake. Observed increments in HPV vaccination hesitancy and refusal were reported by 17.1% and 14.8% of HCPs, respectively. Among HCPs who observed increased hesitancy and refusal, difficulties in scheduling clinic visit during the pandemic and fear of contracting corona virus during the clinic visit were the most cited reasons. Discussion: Findings of the index study suggest that the COVID-19 pandemic has had a negative impact on HPV vaccination in Texas. Results identify perceived barriers to HPV vaccination unique to the pandemic. With the pandemic still ongoing, amid the emergence of novel strains with heightened virulence, despite the presence of highly effective FDA-approved vaccines, findings of this study provides useful insight for public health interventions, as well as to guide physician-patient interactions around HPV vaccination. Citation Format: Onyema Chido-Amajuoyi, Mala Pande, Robert Yu, Sanjay Shete. COVID-19 & cancer prevention in Texas: Reasons cited for HPV vaccination hesitancy and refusal during the pandemic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 435.

The BRAF kinase is a critical node in the MAPK signaling pathway and is mutated in approximately 8% of human cancers including melanoma (~60%), thyroid (~60%), and lung adenocarcinoma (~10%). The most common mutation in BRAF is V600E (Class I), occurring in half of malignant melanomas. This mutation hyperactivates ERK and signals as a RAF inhibitor-sensitive monomer. BRAF inhibitors including vemurafenib, dabrafenib and encorafenib have produced impressive responses in V600X patients, however resistance usually emerges within a year, including RAS mutation, BRAFV600E amplification, and BRAFV600E intragenic deletion or splice variants. These inhibitors are also ineffective against non-V600 BRAF mutants (Class II & III). To address some of these limitations we have developed CFT1946, a bifunctional degradation activating compound (BiDAC™) degrader comprising a BRAF kinase domain targeting ligand linked to a cereblon ligand. CFT1946 is capable of degrading BRAF V600E (Class I), G469A (Class II), G466V (Class III) mutations, and the p61-BRAFV600E splice variant while maintaining exquisite selectivity against the proteome including WT BRAF and CRAF. In A375 cells, CFT1946 potently degraded BRAFV600E (Emax = 26%; DC50 = 14nM at 24hr) and, inhibited ERK phosphorylation (IC50 = 11nM at 24hr) and cell growth (GI50 = 94nM at 96hr) while having no effect in the mutant KRAS driven cell line HCT116. In A375 xenografts, oral delivery of CFT1946 resulted in deeper tumor regressions when dosed at 10 mg/kg PO BID and compared favorably to a clinically relevant dose of encorafenib. We further evaluated CFT1946 in an engineered A375-BRAFV600E/NRASQ61K double mutant model of BRAF inhibitor resistance. CFT1946 was able to degrade BRAFV600E in these cells and was much more effective than encorafenib at inhibiting viability in vitro. In this model, in vivo dosing of single agent CFT1946 caused robust tumor growth inhibition and combination with the MEK inhibitor, trametinib, resulted in tumor regressions. The combination of encorafenib and trametinib showed no activity in the same model. Next, we demonstrated that CFT1946 was able to degrade additional BRAF mutant proteins including G469A (Class II), G466V (Class III), and the p61-BRAFV600E splice variant using heterologous expression in HEK293T cells. Additionally, we also showed that CFT1946, but not encorafenib, inhibited proliferation of the BRAFG466V heterozygous lung tumor cell line H1666. Based on its activity in preclinical models, including models of BRAF inhibitor resistance, and its drug-like properties we are progressing CFT1946 as a candidate for clinical development in patients with solid tumors bearing BRAF V600X mutations. Further, given CFT1946’s activity on non-V600 BRAF mutations, we are continuing to explore CFT1946 and related BiDAC degraders as therapeutic options for patients bearing Class II or Class III BRAF mutations. Citation Format: Mathew E. Sowa, Bridget Kreger, Joelle Baddour, Yanke Liang, Jeffrey R. Simard, Laura Poling, Ping Li, Robert Yu, Ashley Hart, Roman V. Agafonov, Grace Sarkissian, Joe Sahil Patel, Richard Deibler, Kyle S. Cole, Scott Eron, David Cocozziello, Fazlur Rahman, Moses Moustakim, Christopher G. Nasveschuk, Katrina L. Jackson, Mark Fitzgerald, Victoria Garza, Morgan O’Shea, Gesine Veits, Jeremy L. Yap, Andrew J. Phillips, Elizabeth Norton, Adam S. Crystal, Stewart L. Fisher, Roy M. Pollock. Preclinical evaluation of CFT1946 as a selective degrader of mutant BRAF for the treatment of BRAF driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2158.

Functional Dyspepsia (FD) is a common functional gastrointestinal disease, which can reduce the quality of life in patients. Prior research has indicated that insula is closely related to FD and that acupuncture can regulate the functional connectivity (FC) of FD. Therefore, we hypothesized that acupuncture on FD was effected through the insular pathway. To test our hypothesis, we performed electroacupuncture (EA) on FD rat models and then examined the FC between insula and other brain regions through resting-state functional magnetic resonance imaging (rs-fMRI). Seven-day-old male infant Sprague-Dawley (SD) rats were randomly divided into control group, FD model group, and FD acupuncture group, with twelve rats per group (n = 36). Upon establishing successful models, the FD acupuncture group was subjected to EA intervention using Stomach back-shu (BL-21) and front-mu (RN-12) points for ten consecutive days for durations of 20 minutes each day. After intervention, each group was subject to rs-fMRI. The digital image data obtained were analyzed using FC analysis methods. Subsequently, gastric ligation was performed to measure gastric emptying rates. Before EA intervention, the FD model group exhibited decreased functional connections between the insula and a number of brain regions. After EA intervention, FD acupuncture group exhibited increasing FC between insula and regions when compared to the FD model group, such as the primary somatosensory cortex (S1), hippocampal CA3 (CA3), polymorphic layer of dentate gyrus (PoDG), caudate putamen (CPu), and oral pontine reticular nuclei (PnO) P < 0.05 ; decreasing FC was also exhibited between insula and regions such as the bilateral primary and secondary motor cortexes (M1/2), paraventricular hypothalamic nucleus (PVA), and limbic cortex (LC). These findings indicate that the effective treatment of FD using EA may be through regulating the abnormal FC between insula and several brain regions, in particular CA3, PoDG, and PVA.

Background Current understanding of genetic factors associated with pain severity, and improvement of pain with opioids in advanced cancer patients (AC) is inadequate for delivery of personalized pain therapy (PPT). Therefore, the aim of this study was to determine the genetic factors associated with pain severity, daily opioid dose, and pain response in AC patients receiving supportive care. Methods In this prospective study, AC patients were eligible if they had cancer pain ≥4/10 on Edmonton Symptom Assessment Scale (ESAS) - Pain Item and needed opioid rotation for pain control by specialist at the outpatient supportive care center. Association of genetic factors with pain phenotype was assessed using logistic regression models and SKATO (Gene-block) analysis. Results About 174/178 (98%) patient samples were analyzed. After adjustment for demographic and clinical variables, pain severity was negatively associated with intron variant alleles in OPRM1 rs9322446, P = 0.02; rs2270459, P = 0.038; rs62052210, P = 0.038. Opioid daily dose was positively associated NFKBIA rs2233419, P = 0.008; rs2233417, P = 0.007; rs3138054, P = 0.008; rs1050851, P = 0.015; ORPM1 rs9479759, P = 0.046; rs2003185, P = 0.047; rs636433, P = 0.044; COMT (rs9306234, P = 0.014; rs165728, P = 0.014; rs2020917, P = 0.036; rs165728, P = 0.034); ARRB2 (rs1045280, P = 0.045); and pain response to opioids was negatively associated OPRM1 rs1319339, P = 0.024; rs34427887, P = 0.048; and COMT rs4646316, P = 0.03; rs35478083, P = 0.028, respectively. SKATO analysis showed association between pain severity and CXCL8 (P = 0.0056), and STAT6 (P = 0.0297) genes respectively, and pain response with IL-6 (P = 0.00499). Conclusions This study identified that SNPs of OPRM1, COMT, NFKBIA, CXCL8, IL-6, STAT6, and ARRB2 genes were associated with pain severity, opioid daily dose, and pain response in AC receiving supportive care. Additional studies are needed to validate our findings for PPT.