Abstract
Cervical cancer (CC) is caused by oncogenic human papillomaviruses (HR-HPVs) infection and exhibits well-defined clinical stages associated with different steps of tumorigenesis. Screening ...for CC based on HPV is more effective than cytology, but it may increase costs and over treatment of spontaneously regressive high-grade lesions (hgCIN). Thus triage of HPV positive women is needed. Several microRNAs (miRNAs) are dysregulated in CC and hgCIN. However, the studies so far are based on miRNA candidate genes or array approach, mainly in tumor/healthy tissues. The aim of this study is to investigate, for the first time, miRNA profiles by next-generation sequencing in exfoliated cervical cells of HPV-positive women in relation to the presence of hgCIN lesions or as predictors of persistence/progression of CIN lesions. The study is nested in a large Italian multi-centre randomised controlled trial recruiting women in population-based screening programs that actively invite women aged 25-64 years. The study population includes HPV-positive women with CIN2 and CIN3 or without hgCIN lesion. For the discovery phase libraries of 100 samples of exfoliated cervical cells have been set up for miRNA sequencing. For the validation an additional set of 250 samples has already been selected.
Preliminary results shows that, after correction for multiple testing, 44 miRNAs resulted dysregulated in women with vs. those without prevalent hgCIN. This set includes some miRNAs previously reported in the literature, such as miR-100 and miR-126, and other additional miRNAs not included in arrays before. The association of miRNAs with occurrence of hgCIN and clearance of infection during follow up reveals other significantly differentially expressed miRNAs under investigation for their biological roles. The high stability of miRNAs, in contrast to the fast degradation of mRNA and proteins, allows their accurate determination also in samples of exfoliated cervical collected during screening. Validation of the results, associations with other investigated markers and with HPV genotypes will be performed.
Study supported by Italian Association on Cancer Research (AIRC, IG2013 N.14119).
Citation Format: Alessio Naccarati, Daniela De Maria, Francesca Cordero, Barbara Pardini, Stavrula Gouzounis, Maddalena Arigoni, Raffaella Rizzolo, Laura De Marco, Anna Gillio-Tos, Paolo Vineis, Guglielmo Ronco. miRNA as markers of CIN risk and persistence for optimization of HPV-based cervical cancer screening. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-366.
Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism ...loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3′-flanking SNP near ADH1A (rs1230025) and GC risk allelic odds ratio (OR)A v T = 1.30, 95% confidence interval (CI) = 1.07-1.59. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (ORT v C = 0.59; 95% CI = 0.38-0.91 and ORT v C = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (ORA+T = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (<5 g/day: ORA = 0.89, 95% CI = 0.57-1.39; ≥5 g/day: ORA = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.
Abstract
Bladder cancer (BC) is the sixth most commonly diagnosed tumor worldwide. DNA repair capacity (DRC) refers to the ability of a cell to protect the integrity of the genome and DNA repair ...pathways have been implicated in BC risk. It has been observed that individuals with low DRC tend to accumulate more damage than those with a more efficient DRC. This inter-individual variability is modulated by the genetic background, as well as differential gene expression and epigenetic regulation.
We aimed at studying the relationship between DRC and DNA damage (evaluated by H2AX phosphorylation and micronucleus assays) and BC risk and clinical outcome, integrating with gene expression and epigenetic profile data in 159 BC cases and 159 matched controls, enrolled in the Turin Bladder Cancer Study (TBCS).
We investigated ã-H2AX phosphorylation levels and MN frequencies in cryopreserved peripheral blood mononuclear cells. We found significant differences in micronuclei and nuclear buds frequencies, with higher number of these damages in cases compared to controls (p = 0.0002 and p = 0.002 respectively).
On the other hand, we observed a significant association between ã-H2AX basal levels and risk of disease recurrence/progression in both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) (for all BC HR 0.70, 95% CI 0.52-0.94, p = 0.02; for NMIBC HR 0.68, 95% CI 0.50-0.92, p = 0.01): this suggests a protective effect of DNA double strand breaks signalling in terms of preventing BC recurrence or progression.
In order to evaluate the genetic and epigenetic role in modulation of DRC we performed whole genome methylation and gene expression analyses on the same BC cases and controls. Preliminary analyses on methylation levels did not show any significant difference between cases and controls. Two metalloproteinases (MMP23A and MMP23B) resulted significantly under-expressed in BC compared to healthy controls (logFC = -0.23, p = 0.01; logFC = -0.37, p = 0.007, respectively). Interestingly, the expression levels of these genes were also significantly correlated with the relative CpGs methylation.
Further analyses focusing on the integration of whole genome data with DRC assays are ongoing to unravel new prognostic biomarkers of disease.
Citation Format: Giuseppe Matullo, Clara Viberti, Barbara Pardini, Alessandra Allione, Simonetta Guarrera, Valentina Turinetto, Claudia Giachino, Giovanni Fiorito, Alessio Naccarati, Alessia Russo, Rossana Critelli, Paolo Destefanis, Marco Oderda, Paolo Gontero, Paolo Vineis, Carlotta Sacerdote. DNA repair capacity, chromosomal damage, methylation and gene expression levels in bladder cancer: An integrated analysis. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 778.
There is a growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, no prospective study has yet investigated its influence on lymphoma. We evaluated the association ...between adherence to the MD and risk of lymphoma and its subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The analysis included 476,160 participants, recruited from 10 European countries between 1991 and 2001. Adherence to the MD was estimated through the adapted relative MD (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for potential confounders. During an average follow‐up of 13.9 years, 3,136 lymphomas (135 Hodgkin lymphoma HL, 2,606 non‐HL and 395 lymphoma not otherwise specified) were identified. Overall, a 1‐unit increase in the arMED score was associated with a 2% lower risk of lymphoma (95% CI: 0.97; 1.00, p‐trend = 0.03) while a statistically nonsignificant inverse association between a high versus low arMED score and risk of lymphoma was observed (hazard ratio HR: 0.91 95% CI 0.80; 1.03, p‐trend = 0.12). Analyses by lymphoma subtype did not reveal any statistically significant associations. Albeit with small numbers of cases (N = 135), a suggestive inverse association was found for HL (HR 1‐unit increase = 0.93 95% CI: 0.86; 1.01, p‐trend = 0.07). However, the study may have lacked statistical power to detect small effect sizes for lymphoma subtype. Our findings suggest that an increasing arMED score was inversely related to the risk of overall lymphoma in EPIC but not by subtypes. Further large prospective studies are warranted to confirm these findings.
What's new?
Known risk factors explain only a small proportion of lymphoma cases. Several studies have pointed out the potential role of dietary factors on lymphoma risk, but evidence is still inconclusive. Here, using data from the European Prospective Investigation into Cancer and Nutrition study, the authors found for the first time that adherence to a Mediterranean diet was modestly associated with a reduced risk of overall lymphoma. Further studies are needed to confirm these findings.
Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer.
We conducted a nested case-control study within the ...European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk.
Tryptophan (Ptrend = 2 × 10(-5)) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 × 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 95% confidence interval (CI), 0.37-0.74 for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, Ptrend = 3 × 10(-5)) that was only marginally affected by adjusting for methionine.
This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology.
This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.
We examined the associations of intake of vegetables, legumes and fruit with all-cause and cause-specific mortality in a population with prevalent diabetes in Europe. A cohort of 10,449 participants ...with self-reported diabetes within the European Prospective Investigation into Cancer and Nutrition study was followed for a mean of 9 y. Intakes of vegetables, legumes, and fruit were assessed at baseline between 1992 and 2000 using validated country-specific questionnaires. A total of 1346 deaths occurred. Multivariate relative risks (RR) for all-cause mortality were estimated in Cox regression models and RR for cause-specific mortality were derived in a competing risk model. An increment in intake of total vegetables, legumes, and fruit of 80 g/d was associated with a RR of death from all causes of 0.94 95% CI 0.90-0.98. Analyzed separately, vegetables and legumes were associated with a significantly reduced risk, whereas nonsignificant inverse associations for fruit intake were observed. Cardiovascular disease (CVD) mortality and mortality due to non-CVD/non-cancer causes were significantly inversely associated with intake of total vegetables, legumes, and fruit (RR 0.88 95% CI 0.81-0.95 and 0.90 0.82-0.99, respectively) but not cancer mortality (1.08 0.99-1.17). Intake of vegetables, legumes, and fruit was associated with reduced risks of all-cause and CVD mortality in a diabetic population. The findings support the current state of evidence from general population studies that the protective potential of vegetable and fruit intake is larger for CVD than for cancer and suggest that diabetes patients may benefit from a diet high in vegetables and fruits.
Urinary metabolic profiling is a promising powerful tool to reflect dietary intake and can help understand metabolic alterations in response to diet quality. Here, we used
H NMR spectroscopy in a ...multicountry study in European children (1147 children from 6 different cohorts) and identified a common panel of 4 urinary metabolites (hippurate,
-methylnicotinic acid, urea, and sucrose) that was predictive of Mediterranean diet adherence (KIDMED) and ultra-processed food consumption and also had higher capacity in discriminating children's diet quality than that of established sociodemographic determinants. Further, we showed that the identified metabolite panel also reflected the associations of these diet quality indicators with C-peptide, a stable and accurate marker of insulin resistance and future risk of metabolic disease. This methodology enables objective assessment of dietary patterns in European child populations, complementary to traditional questionary methods, and can be used in future studies to evaluate diet quality. Moreover, this knowledge can provide mechanistic evidence of common biological pathways that characterize healthy and unhealthy dietary patterns, and diet-related molecular alterations that could associate to metabolic disease.
Abstract
During the last decades, improvements in medical and surgical treatments have substantially increased the chances of surviving from a cancer. Cancer survivors now amount to more than 3.5% of ...population in the US, and about 3% in Western Europe. Cancer survivors face the problem of subsequent cancers possibly related to the late effects of treatments or to a common aetiology for the first and subsequent cancers. Cancer patients have a 20% higher risk of new primary cancer compared with the general population. Approximately one third of cancer survivors aged >60 years were diagnosed more than once with another cancer. Women with breast cancer as first primary cancer were the first largest group of multiple cancer prevalence reported in the United States in 2002, while the second and third groups were men and women with a diagnosis of primary colorectal cancer and men with prostate cancer, respectively. Multiple cancers arise in the same individual due to several causes: host factors, such as hormonal and/or genetic factors, lifestyle and environment, and treatments due to the first cancer (for example, radiotherapy) The aim of this study is to assess the incidence of second primary tumors in a cohort of women with a first breast cancer and to investigate the role of shared risk factors. The study was performed in the cohort of women with a primary breast cancer from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. To correctly assess the incidence of second primary tumors, we applied a Markov model studying the transition intensities from first to second tumor with the Aalen-Johansen (AJ) estimators, as usually done in competing risk models. In the cohort of 11045 women, we observed 492 second primary tumors (not metachronous) after a median follow-up of 4.92 years. About 30% (140) of them were second primary breast cancers, 65 were colorectal cancers and 39 were endometrial cancers. In this cohort, there was a slight, not statistically significant increase of cancer incidence in women with breast cancer, compared to the general population; this was for all tumors together, except non-melanoma skin cancers. Analysis by subgroups identified a significant increase for second breast cancers and for endometrial cancers. Our findings suggest that second primaries may be an important problem for cancer survivors. We will now investigate the role played by lifestyle factors, genetics and possibly therapies in second primary occurrence.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3585. doi:1538-7445.AM2012-3585
The etiologies of glioma and meningioma tumors are largely unknown. Although reproductive hormones are thought to influence the risk of these tumors, epidemiologic data are not supportive of this ...hypothesis; however, few cohort studies have published on this topic. We examined the relation between reproductive factors and the risk of glioma and meningioma among women in the European Prospective Investigation into Cancer and Nutrition (EPIC).
After a mean of 8.4 years of follow-up, 193 glioma and 194 meningioma cases were identified among 276,212 women. Information on reproductive factors and hormone use was collected at baseline. Cox proportional hazard regression was used to determine hazard ratios (HR) and 95% confidence intervals (95% CI).
No associations were observed between glioma or meningioma risk and reproductive factors, including age at menarche, parity, age at first birth, menopausal status, and age at menopause. A higher risk of meningioma was observed among postmenopausal women who were current users of hormone replacement therapy (HR, 1.79; 95% CI, 1.18-2.71) compared with never users. Similarly, current users of oral contraceptives were at higher risk of meningioma than never users (HR, 3.61; 95% CI, 1.75-7.46).
Our results do not support a role for estrogens and glioma risk. Use of exogenous hormones, especially current use, seems to increase meningioma risk. However, these findings could be due to diagnostic bias and require confirmation.
Elucidating the role of hormones in brain tumor development has important implications and needs to be further examined using biological measurements.
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