Cancer prevention research (Philadelphia, Pa.)最新文献

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.

Prevention relevance: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.

The incidence of second primary cancers is rising particularly among pediatric, adolescent, and young adult (PAYA) cancer survivors. While human papillomavirus (HPV)-associated cancers can be prevented by vaccination, their uptake is lower and delayed in this group. Because a recommendation from a health care provider is the strongest predictor of HPV vaccination, there are great opportunities for PAYA cancer care providers to positively impact HPV vaccination rates. Prioritizing PAYA cancer care provider education as well as improving the education of and coordination with primary care providers are viewed as opportunities to encourage HPV vaccine uptake and prevent future cancers. See related article by Garcia et al., p. 581.

Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.

Health behavior theories have identified predictors of colorectal cancer screening. This study aimed to determine the psychosocial profiles of a predominantly Hispanic population of primarily Mexican origin receiving a colorectal cancer screening intervention and whether a specific combination of psychosocial profiles modified the effect of colorectal cancer screening intervention on colorectal cancer screening uptake.A total of 467 participants aged 50 to 75 years due for colorectal cancer screening received an educational intervention. Latent profile analysis (LPA) was performed on baseline psychosocial constructs to identify the homogenous clustering of individuals with similar psychosocial constructs. In addition, colorectal cancer screening rates and changes in psychosocial scores between the latent groups were compared.Three psychosocial profiles, including a low benefit and high susceptibility group (LBHS), a high benefit and low susceptibility group (HBLS), and a high barrier and high susceptibility group (HBHS), were identified in this study. The HBLS group had the lowest susceptibility, with no improvement in benefits and barriers. This group had the lowest screening rate (80.85%) compared with 88.8% in LBHS and 86.3% in HBHS following the intervention. Finally, the intervention effect size on psychosocial score changes was smaller in HBLS than in other groups.This subgroup analysis suggests that colorectal cancer educational interventions should be tailored to improve the benefits and barriers among individuals with high susceptibility scores.

Prevention relevance: This LPA analysis provides some direction for tailoring colorectal cancer educational interventions to improve the benefits and barriers among individuals with high susceptibility scores in hard-to-screen populations such as our border population.

We summarize Siteman Cancer Center catchment that covers 82 counties in southern Illinois and eastern Missouri. We note both the high poverty and cancer rates in many rural counties. Siteman Community Outreach and Engagement has developed a number of strategies to move towards achieving health equity. These include NCI-funded research projects in rural clinics and outreach to improve access to cancer prevention services. To increase capacity for community-engaged research, we have developed and refined a Community Research Fellows Training Program.

Cancer immunoprevention applies immunologic approaches such as vaccines to prevent, rather than to treat or cure, cancer. Despite limited success in the treatment of advanced disease, the development of cancer vaccines to intercept premalignant states is a promising area of current research. These efforts are supported by the rationale that vaccination in the premalignant setting is less susceptible to mechanisms of immune evasion compared with established cancer. Prophylactic vaccines have already been developed for a minority of cancers mediated by oncogenic viruses (e.g., hepatitis B and human papillomavirus). Extending the use of preventive vaccines to non-virally driven malignancies remains an unmet need to address the rising global burden of cancer. This review provides a broad overview of clinical trials in cancer immunoprevention with an emphasis on emerging vaccine targets and delivery platforms, translational challenges, and future directions.

Subclinical liver impairment due to fibrosis could influence the development and detectability of prostate cancer. To investigate the association between liver fibrosis and prostate cancer incidence and mortality, we included 5,284 men (mean age: 57.6 years, 20.1% Black) without cancer or liver disease at Visit 2 in the Atherosclerosis Risk in Communities study. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index, fibrosis 4 index (FIB-4), and nonalcoholic fatty liver disease fibrosis score (NFS). Over 25 years, 215 Black and 511 White men were diagnosed with prostate cancer, and 26 Black and 51 White men died from the disease. We estimated HRs for total and fatal prostate cancer using Cox regression. FIB-4 [quintile 5 vs. 1: HR = 0.47, 95% confidence interval (CI): 0.29-0.77, Ptrend = 0.004] and NFS (HR = 0.56, 95% CI: 0.33-0.97, Ptrend = 0.03) were inversely associated with prostate cancer risk in Black men. Compared with no abnormal score, men with ≥1 abnormal score had a lower prostate cancer risk if they were Black (HR = 0.46, 95% CI: 0.24-0.89), but not White (HR = 1.04, 95% CI: 0.69-1.58). Liver fibrosis scores did not appear to be associated with fatal prostate cancer in Black or White men. Among men without a clinical diagnosis of liver disease, higher liver fibrosis scores were associated with lower incidence of prostate cancer in Black men, but not in White men, and not with fatal prostate cancer in either race. Further research is needed to understand the influence of subclinical liver disease on prostate cancer development versus detectability and the racial differences observed.

Prevention relevance: Investigating the link between liver fibrosis and prostate cancer risk and mortality, our study reveals the potential influence of liver health on prostate cancer development and on detection using PSA test, urging further research to understand the differential findings by race and to optimize prevention and intervention strategies.

Early-onset colorectal cancer (EOCRC) is increasing at alarming rates and identifying risk factors is a high priority. There is a need to develop risk stratification approaches for colorectal cancer screening among younger populations. Although there is a growing body of evidence identifying risk factors for EOCRC, including the report by Imperiale and colleagues in this issue, risk stratification for EOCRC screening has not been implemented into practice. This publication highlights how essential it is to bring research findings into practice and bridge the gaps between developing risk prediction modeling in epidemiology and implementation science. While encouraging, we are still a long way off from having a clinically applicable risk prediction tool. See related article by Imperiale et al., p. 513.

Identifying risk factors for early-onset colorectal cancer (EOCRC) could help reverse its rising incidence through risk factor reduction and/or early screening. We sought to identify EOCRC risk factors that could be used for decisions about early screening. Using electronic databases and medical record review, we compared male veterans ages 35 to 49 years diagnosed with sporadic EOCRC (2008-2015) matched 1:4 to clinic and colonoscopy controls without colorectal cancer, excluding those with established inflammatory bowel disease, high-risk polyposis, and nonpolyposis syndromes, prior bowel resection, and high-risk family history. We ascertained sociodemographic and lifestyle factors, family and personal medical history, physical measures, vital signs, medications, and laboratory values 6 to 18 months prior to case diagnosis. In the derivation cohort (75% of the total sample), univariate and multivariate logistic regression models were used to derive a full model and a more parsimonious model. Both models were tested using a validation cohort. Among 600 cases of sporadic EOCRC [mean (SD) age 45.2 (3.5) years; 66% White], 1,200 primary care clinic controls [43.4 (4.2) years; 68% White], and 1,200 colonoscopy controls [44.7 (3.8) years; 63% White], independent risk factors included age, cohabitation and employment status, body mass index (BMI), comorbidity, colorectal cancer, or other visceral cancer in a first- or second-degree relative (FDR or SDR), alcohol use, exercise, hyperlipidemia, use of statins, NSAIDs, and multivitamins. Validation c-statistics were 0.75-0.76 for the full model and 0.74-0.75 for the parsimonious model, respectively. These independent risk factors for EOCRC may identify veterans for whom colorectal cancer screening prior to age 45 or 50 years should be considered.

Prevention relevance: Screening 45- to 49-year-olds for colorectal cancer is relatively new with uncertain uptake thus far. Furthermore, half of EOCRC occurs in persons < 45 years old. Using risk factors may help 45- to 49-year-olds accept screening and may identify younger persons for whom earlier screening should be considered. See related Spotlight, p. 479.

Mammographic percentage of volumetric density is an important risk factor for breast cancer. Epidemiology studies historically used film images often limited to craniocaudal (CC) views to estimate area-based breast density. More recent studies using digital mammography images typically use the averaged density between craniocaudal (CC) and mediolateral oblique (MLO) view mammography for 5- and 10-year risk prediction. The performance in using either and both mammogram views has not been well-investigated. We use 3,804 full-field digital mammograms from the Joanne Knight Breast Health Cohort (294 incident cases and 657 controls), to quantity the association between volumetric percentage of density extracted from either and both mammography views and to assess the 5 and 10-year breast cancer risk prediction performance. Our results show that the association between percent volumetric density from CC, MLO, and the average between the two, retain essentially the same association with breast cancer risk. The 5- and 10-year risk prediction also shows similar prediction accuracy. Thus, one view is sufficient to assess association and predict future risk of breast cancer over a 5 or 10-year interval.

Prevention relevance: Expanding use of digital mammography and repeated screening provides opportunities for risk assessment. To use these images for risk estimates and guide risk management in real time requires efficient processing. Evaluating the contribution of different views to prediction performance can guide future applications for risk management in routine care.