Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.

Radiomics analysis to predict pulmonary nodule malignancy using machine learning approaches.

BACKGROUND: Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen. METHODS: Using four international lung cancer screening studies, we extracted 2060 radiomic features for each of 16 797 nodules (513 malignant) among 6865 participants. After filtering out low-quality radiomic features, 642 radiomic and 9 epidemiological features remained for model development. We used cross-validation and grid search to assess three machine learning (ML) models (eXtreme Gradient Boosted Trees, random forest, least absolute shrinkage and selection operator (LASSO)) for their ability to accurately predict risk of malignancy for pulmonary nodules. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set. RESULTS: The LASSO model yielded the best predictive performance in cross-validation and was fit in the full training set based on optimised hyperparameters. Our radiomics model had a test-set AUC of 0.93 (95% CI 0.90 to 0.96) and outperformed the established Pan-Canadian Early Detection of Lung Cancer model (AUC 0.87, 95% CI 0.85 to 0.89) for nodule assessment. Our model performed well among both solid (AUC 0.93, 95% CI 0.89 to 0.97) and subsolid nodules (AUC 0.91, 95% CI 0.85 to 0.95). CONCLUSIONS: We developed highly accurate ML models based on radiomic and epidemiological features from four international lung cancer screening studies that may be suitable for assessing indeterminate screen-detected pulmonary nodules for risk of malignancy.

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study.

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore.

BACKGROUND: The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment. METHODS: CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case-control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines-soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1ß), and tumour necrosis factor alpha (TNF-α). RESULTS: sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk. CONCLUSION: sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

Impact of the COVID-19 pandemic on cancer patients in western Pennsylvania: rural-urban disparities.

PURPOSE: Disparities in cancer care persist between patients living in rural versus urban areas. The COVID-19 pandemic may have impacted concerns related to care and personal health differently in rural cancer patients. Using survey data collected from cancer patients in western Pennsylvania, we examined pandemic-related distress, concerns related to cancer care, impact on personal health, and the extent to which these differed by urban-rural residence. METHODS: Patients filled out an initial survey in August-December 2020; a second survey was completed in March 2021. The following patient concerns related to the pandemic were evaluated: threat of COVID-19 to their health, pandemic-related distress, perceptions of cancer care, and vaccine hesitancy. Multivariable logistic regression models were used to examine relationships between these outcomes and urban-rural residence as well as patient-related factors, including anxiety symptoms and social support. RESULTS: The study sample included 1,980 patients, 17% resided in rural areas. COVID-19 represented a major or catastrophic threat to personal health for 39.7% of rural and 49.0% of urban patients (p = 0.0017). Patients with high general anxiety were 10-times more likely to experience pandemic-related distress (p < 0.001). In the follow-up survey (n = 983), vaccine hesitancy was twice as prevalent among rural patients compared to urban (p = 0.012). CONCLUSIONS: The extent to which perceptions of the threat of COVD-19 to personal health and vaccine hesitancy exacerbates rural-urban disparities in cancer care and prognosis warrants further study. Cancer patients may be vulnerable to heightened anxiety and distress triggered by the pandemic.

The microRNA target site landscape is a novel molecular feature associating alternative polyadenylation with immune evasion activity in breast cancer.

Alternative polyadenylation (APA) in breast tumor samples results in the removal/addition of cis-regulatory elements such as microRNA (miRNA) target sites in the 3'-untranslated region (3'-UTRs) of genes. Although previous computational APA studies focused on a subset of genes strongly affected by APA (APA genes), we identify miRNAs of which widespread APA events collectively increase or decrease the number of target sites [probabilistic inference of microRNA target site modification through APA (PRIMATA-APA)]. Using PRIMATA-APA on the cancer genome atlas (TCGA) breast cancer data, we found that the global APA events change the number of the target sites of particular microRNAs [target sites modified miRNA (tamoMiRNA)] enriched for cancer development and treatments. We also found that when knockdown (KD) of NUDT21 in HeLa cells induces a different set of widespread 3'-UTR shortening than TCGA breast cancer data, it changes the target sites of the common tamoMiRNAs. Since the NUDT21 KD experiment previously demonstrated the tumorigenic role of APA events in a miRNA dependent fashion, this result suggests that the APA-initiated tumorigenesis is attributable to the miRNA target site changes, not the APA events themselves. Further, we found that the miRNA target site changes identify tumor cell proliferation and immune cell infiltration to the tumor microenvironment better than the miRNA expression levels or the APA events themselves. Altogether, our computational analyses provide a proof-of-concept demonstration that the miRNA target site information indicates the effect of global APA events with a potential as predictive biomarker.

Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations.

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Early natural menopause is associated with poor lung health and increased mortality among female smokers.

BACKGROUND: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies. OBJECTIVE: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers. STUDY DESIGN: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis. RESULTS: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause. CONCLUSION: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.

Integrated Biomarkers for the Management of Indeterminate Pulmonary Nodules.

Rationale: Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model that combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods: In this prospectively collected, retrospective blinded evaluation study, probability of cancer was calculated for 456 patient nodules using the Mayo Clinic model, and patients were categorized into low-, intermediate-, and high-risk groups. A combined biomarker model (CBM) including clinical variables, serum high sensitivity CYFRA 21-1 level, and a radiomic signature was trained in cohort 1 (n = 170) and validated in cohorts 2-4 (total n = 286). All patients were pooled to recalibrate the model for clinical implementation. The clinical utility of the CBM compared with current clinical care was evaluated in 2 cohorts. Measurements and Main Results: The CBM provided improved diagnostic accuracy over the Mayo Clinic model with an improvement in area under the curve of 0.124 (95% bootstrap confidence interval, 0.091-0.156; P < 2 × 10-16). Applying 10% and 70% risk thresholds resulted in a bias-corrected clinical reclassification index for cases and control subjects of 0.15 and 0.12, respectively. A clinical utility analysis of patient medical records estimated that a CBM-guided strategy would have reduced invasive procedures from 62.9% to 50.6% in the intermediate-risk benign population and shortened the median time to diagnosis of cancer from 60 to 21 days in intermediate-risk cancers. Conclusions: Integration of clinical, blood, and image biomarkers improves noninvasive diagnosis of patients with IPNs, potentially reducing the rate of unnecessary invasive procedures while shortening the time to diagnosis.

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Tumor-Derived Exosomes (TEX) and Their Role in Immuno-Oncology.

Extracellular vesicles (EVs) play a key role in health and disease, including cancer. Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30-150 nm (virus-size) vesicles originating from the multivesicular bodies (MVBs) and carrying a cargo that in its content and topography approximates that of a parent cell. Tumor-derived exosomes (TEX) present in all body fluids of cancer patients, are considered promising candidates for a liquid tumor biopsy. TEX also mediate immunoregulatory activities: they maintain a crosstalk between the tumor and various non-malignant cells, including immunocytes. Effects that EVs exert on immune cells may be immunosuppressive or immunostimulatory. Here, we review the available data for TEX interactions with immunocytes, focusing on strategies that allow isolation from plasma and separation of TEX from sEV produced by non-malignant cells. Immune effects mediated by either of the subsets can now be distinguished and measured. The approach has allowed for the comparison of molecular and functional profiles of the two sEV fractions in plasma of cancer patients. While TEX carried an excess of immunosuppressive proteins and inhibited immune cell functions in vitro and in vivo, the sEV derived from non-malignant cells, including CD3(+)T cells, were variably enriched in immunostimulatory proteins and could promote functions of immunocytes. Thus, sEV in plasma of cancer patients are heterogenous, representing a complex molecular network which is not evident in healthy donors' plasma. Importantly, TEX appear to be able to reprogram functions of non-malignant CD3(+)T cells inducing them to produce CD3(+)sEV enriched in immunosuppressive proteins. Ratios of stimulatory/inhibitory proteins carried by TEX and by CD3(+)sEV derived from reprogrammed non-malignant cells vary broadly in patients and appear to negatively correlate with disease progression. Simultaneous capture from plasma and functional/molecular profiling of TEX and the CD3(+)sEV fractions allows for defining their role as cancer biomarkers and as monitors of cancer patients' immune competence, respectively.

Prevalence of colorectal cancer and advanced adenoma in patients with acute diverticulitis: implications for follow-up colonoscopy.

BACKGROUND AND AIMS: Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy. METHODS: CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573). RESULTS: A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P < .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%). CONCLUSIONS: CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

Primary Care Providers' Knowledge, Attitudes, Beliefs, and Practices Regarding Their Preparedness to Provide Cancer Survivorship Care.

Recent cancer care delivery models and clinical practice guidelines have expanded the role of primary care providers (PCPs) in routine follow-up of cancer survivors. We conducted a cross-sectional survey of PCPs affiliated with a large healthcare system to (1) examine practices, attitudes, and beliefs regarding preparedness to provide survivorship care and (2) explore predictors of confidence managing cancer survivors. We distributed a self-administered online survey to 1069 clinical affiliates providing primary care services within the University of Pittsburgh Medical Center system. Associations between PCPs' professional characteristics and attitudes and preparedness were evaluated. Multiple logistic regression explored predictors of confidence monitoring common cancer treatment-related symptoms. One hundred twenty-seven eligible PCPs responded. The sample was split between academic and community practice (48.0% vs. 52.0%, respectively), predominantly comprised of physicians (81.8%), and 64.6% had > 15 years direct patient care experience. The majority agreed that PCPs play a valuable role in surveillance and adverse event monitoring in survivors, though less than 25% felt their professional training prepared them to perform each of these domains. Physicians were significantly more likely than advanced practice providers to be among the 65% of PCPs who were confident monitoring ≥ 1 symptom in each of the 5 evaluated symptom clusters (OR 3.6, 95% CI 1.2-10.8). PCPs appear willing to assume an enhanced role in cancer survivorship care but feel unprepared to do so. Enhanced training and dissemination of clinical practice guidelines are needed to facilitate effective implementation of PCP-delivered survivorship care.

Joint exposure to smoking, excessive weight, and physical inactivity and survival of ovarian cancer patients, evidence from the Ovarian Cancer Association Consortium.

PURPOSE: Previous epidemiologic studies have shown that smoking, obesity, and physical inactivity are associated with poor survival following a diagnosis of ovarian cancer. Yet, the combined relationship of these unfavorable lifestyle factors on ovarian cancer survival has not been sufficiently investigated. METHODS: Using data pooled from 13 studies, we examined the associations between combined exposures to smoking, overweight/obesity weight, and physical inactivity and overall survival (OS) as well as progression-free survival (PFS) among women diagnosed with invasive epithelial ovarian carcinoma (n = 7,022). Using age- and stage-adjusted Cox proportional hazards regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) associated with joint exposure to these factors. RESULTS: Combined exposure to current smoking, overweight/obesity, and physical inactivity prior to diagnosis was associated with a significantly increased risk of mortality compared to women who never smoked, had normal body mass index (BMI), and were physically active (HR = 1.37; 95% CI 1.10-1.70). The association for a joint exposure to these factors exceeded that of each exposure individually. In fact, exposure to both current smoking and overweight/obesity, and current smoking and physical inactivity was also associated with increased risk of death (HR = 1.28; 95% CI 1.08-1.52, and HR = 1.26; 95% CI 1.04-1.54, respectively). The associations were of a similar magnitude when former smoking was assessed in combination with the other exposures and when excessive weight was limited to obesity only. No significant associations were observed between joint exposure to any of these factors and PFS. CONCLUSIONS: Joint exposure to smoking, excessive weight, and physical inactivity may negatively impact survival of ovarian cancer patients. These results suggest the importance of examining the combined effect of lifestyle factors on ovarian cancer patients' survival.

Gene Promoter Hypermethylation Detected in Sputum Predicts FEV1 Decline and All-Cause Mortality in Smokers.

RATIONALE: Gene promoter hypermethylation detected in sputum assesses the extent of field cancerization and predicts lung cancer (LC) risk in ever-smokers. A rapid decline of FEV1 is a major driver for development of airway obstruction. OBJECTIVES: To assess the effects of methylation of 12 genes on FEV1 decline and of FEV1 decline on subsequent LC incidence using two independent, longitudinal cohorts (i.e., LSC [Lovelace Smokers Cohort] and PLuSS [Pittsburgh Lung Screening Study]). METHODS: Gene methylation was measured in sputum using two-stage nested methylation-specific PCR. The linear mixed effects model was used to assess the effects of studied variables on FEV1 decline. MEASUREMENTS AND MAIN RESULTS: A dose-dependent relationship between number of genes methylated and FEV1 decline was identified, with smokers with three or more methylated genes having 27.8% and 10.3% faster FEV1 decline than smokers with zero to two methylated genes in the LSC and PLuSS cohort, respectively (all P < 0.01). High methylation in sputum was associated with a shorter latency for LC incidence (log-rank P = 0.0048) and worse all-cause mortality (log-rank P < 0.0001). Smokers with subsequent LC incidence had a more rapid annual decline of FEV1 (by 5.2 ml, P = 0.038) than smoker control subjects. CONCLUSIONS: Gene methylation detected in sputum predicted FEV1 decline, LC incidence, and all-cause mortality in smokers. Rapid FEV1 decline may be a risk factor for LC incidence in smokers, which may explain a greater prevalence of airway obstruction seen in patients with LC.

Anthropometric characteristics and ovarian cancer risk and survival.

PURPOSE: Multiple studies have examined the role of anthropometric characteristics in ovarian cancer risk and survival; however, their results have been conflicting. We investigated the associations between weight change, height and height change and risk and outcome of ovarian cancer using data from a large population-based case-control study. METHODS: Data from 699 ovarian cancer cases and 1,802 controls who participated in the HOPE study were included. We used unconditional logistic regression adjusted for age, race, number of pregnancies, use of oral contraceptives, and family history of breast or ovarian cancer to examine the associations between self-reported height and weight and height change with ovarian cancer risk. Cox proportional hazards regression models adjusted for age and stage were used to examine the association between the exposure variables and overall and progression-free survival among ovarian cancer cases. RESULTS: We observed an increased risk of ovarian cancer mortality and progression for gaining more than 20 pounds between ages 18-30, HR 1.36; 95% CI 1.05-1.76, and HR 1.31; 95% CI 1.04-1.66, respectively. Losing weight and gaining it back multiple times was inversely associated with both ovarian cancer risk, OR 0.78; 95% CI 0.63-0.97 for 1-4 times and OR 0.73; 95% CI 0.54-0.99 for 5-9 times, and mortality, HR 0.63; 95% CI 0.40-0.99 for 10-14 times. Finally, being taller during adolescence and adulthood was associated with increased risk of mortality. Taller stature and weight gain over lifetime were not related to ovarian cancer risk. CONCLUSIONS: Our results suggest that height and weight and their change over time may influence ovarian cancer risk and survival. These findings suggest that biological mechanisms underlying these associations may be hormone driven and may play an important role in relation to ovarian carcinogenesis and tumor progression.