BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we ...conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 expression in human breast cancers displaying intrinsic or acquired PARP-inhibitor resistance.
Background
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas ...from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross‐culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer‐preventative effects.
Objectives
To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes.
Search methods
We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies.
Selection criteria
We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non‐randomised studies, i.e. observational studies with both cohort and case‐control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both.
Data collection and analysis
Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type.
Main results
In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review.
Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea‐supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low‐certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low‐certainty evidence). No evidence of effect of non‐melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low‐certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies.
In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case‐control studies, which were on average of intermediate to high methodological quality based on Newcastle‐Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low‐certainty evidence). Conversely, we found no association between green tea consumption and cancer‐related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low‐certainty evidence).
For most of the site‐specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case‐control studies.
Authors' conclusions
Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites.
Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case‐control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six ...cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r
= 0.57, p = 4.6 × 10
), breast and ovarian cancer (r
= 0.24, p = 7 × 10
), breast and lung cancer (r
= 0.18, p =1.5 × 10
) and breast and colorectal cancer (r
= 0.15, p = 1.1 × 10
). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Despite progresses in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of gliomas does not yet exist. Mortality is still close to 100% and the average survival of patients ...with GBM is less than 1 year. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood brain barrier. The oncogenesis of gliomas is characterized by several biological processes and genetic alterations, involved in the neoplastic transformation. The modulation of gene expression to more levels, such as DNA, mRNA, proteins and transduction signal pathways, may be the most effective modality to down-regulate or silence some specific gene functions. Gliomas are characterized by extensive microvascular proliferation and a higher degree of vasculature. In malignant gliomas targeted therapies efficacy is low. In this complex field, it seems to be very important to improve specific selective drugs delivery systems. Drugs, antisense oligonucleotides, small interference RNAs, engineered monoclonal antibodies and other therapeutic molecules may diffuse into CNS overcoming the BBB. Nanotechnology could be used both to improve the treatment efficacy and to reduce the adverse side effects.
The registration data of local cancer registries in 2014 were collected by National Central Cancer Registry (NCCR)in 2017 to estimate the cancer incidence and mortality in China.
The data submitted ...from 449 registries were checked and evaluated, and the data of 339 registries out of them were qualified and selected for the final analysis. Cancer incidence and mortality were stratified by area, gender, age group and cancer type, and combined with the population data of 2014 to estimate cancer incidence and mortality in China. The age composition of standard population of Chinese census in 2000 and Segi's population were used for age-standardized incidence and mortality in China and worldwide, respectively.
Total covered population of 339 cancer registries (129 in urban and 210 in rural) in 2014 were 288 243 347 (144 061 915 in urban and 144 181 432 in rural areas). The mortality verified cases (MV%) were 68.01%. Among them, 2.19% cases were identified through death certifications only (DCO%), and the mortality
High-risk human papilloma viruses (HPV) are a causative agent of anogenital and oropharyngeal cancers. Patients treated for a preinvasive or invasive HPV-associated cancer may be at increased risk of ...a second such malignancy.
We performed a systematic review and random effects meta-analysis to estimate the risk of HPV-associated cancer after prior diagnosis. Studies reporting second cancers at anogenital and oropharyngeal sites after prior diagnoses (preinvasive/invasive HPV-associated cancer) were identified. Studies reporting standardised incidence ratios (SIRs) were included in formal meta-analyses of second cancer risk. (PROSPERO ID: CRD42016046974).
Searches returned 5599 titles, including 60 unique, eligible studies. Thirty-two (98 comparisons) presented SIRs for second cervical, anal, vulvo-vaginal, penile, and/or oropharyngeal cancers, included in the meta-analyses. All studies (and 95/98 comparisons) reported increased cancers in the population with previous HPV-associated cancer when compared to controls. Pooled SIRs for second primary cancers ranged from 1.75 (95% CI 0.66-4.67) for cervical cancer after primary anal cancer, to 13.69 (95% CI 8.56-21.89) for anal cancer after primary vulvo-vaginal cancer.
We have quantified the increased risk of second HPV-associated cancer following diagnosis and treatment for initial cancer or preinvasive disease. This has important implications for follow-up, screening, and future therapeutic trials.
Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the ...Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.
Obesity surgery and risk of cancer Mackenzie, H.; Markar, S. R.; Askari, A. ...
British journal of surgery,
November 2018, Letnik:
105, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Background
Obesity increases the risk of several types of cancer. Whether bariatric surgery influences the risk of obesity‐related cancer is not clear. This study aimed to uncover the risk of ...hormone‐related (breast, endometrial and prostate), colorectal and oesophageal cancers following obesity surgery.
Methods
This national population‐based cohort study used data from the Hospital Episode Statistics database in England collected between 1997 and 2012. Propensity matching on sex, age, co‐morbidity and duration of follow‐up was used to compare cancer risk among obese individuals undergoing bariatric surgery (gastric bypass, gastric banding or sleeve gastrectomy) and obese individuals not undergoing such surgery. Conditional logistic regression provided odds ratios (ORs) with 95 per cent confidence intervals.
Results
In the study period, from a cohort of 716 960 patients diagnosed with obesity, 8794 patients who underwent bariatric surgery were matched exactly with 8794 obese patients who did not have surgery. Compared with the no‐surgery group, patients who had bariatric surgery exhibited a decreased risk of hormone‐related cancers (OR 0·23, 95 per cent c.i. 0·18 to 0·30). This decrease was consistent for breast (OR 0·25, 0·19 to 0·33), endometrium (OR 0·21, 0·13 to 0·35) and prostate (OR 0·37, 0·17 to 0·76) cancer. Gastric bypass resulted in the largest risk reduction for hormone‐related cancers (OR 0·16, 0·11 to 0·24). Gastric bypass, but not gastric banding or sleeve gastrectomy, was associated with an increased risk of colorectal cancer (OR 2·63, 1·17 to 5·95). Longer follow‐up after bariatric surgery strengthened these diverging associations.
Conclusion
Bariatric surgery is associated with decreased risk of hormone‐related cancers, whereas gastric bypass might increase the risk of colorectal cancer.
Obesity affects cancer risk
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