Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated ...with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers.
We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio OR 1.80; 95% confidence interval CI 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers.
Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Serrated polyps (SPs) are precursors to one‐third of colorectal cancers (CRCs), with histological subtypes: hyperplastic polyps (HPs), sessile serrated lesions (SSLs) and traditional serrated ...adenomas (TSAs). The incidence of early‐onset CRC before the age of 50 is increasing, with limited understanding of SPs in younger cohorts. Using a large colonoscopy‐based cohort, we characterized epidemiologic profiles of SP subtypes, compared to conventional adenomas, with secondary analysis on early‐onset polyps. Ninety‐four thousand four hundred and twenty‐seven patients underwent screening colonoscopies between 2010 and 2018. Demographic, endoscopic and histopathologic characteristics of each polyp subtype were described. High‐risk polyps included SSLs ≥10 mm/with dysplasia and conventional adenomas ≥10 mm/with tubulovillous/villous histology/high‐grade dysplasia. We examined polyp prevalence with age and compared early‐ (age < 50) and late‐onset polyps (age ≥ 50). Eighteen thousand one hundred and twenty‐five patients had SPs (4357 SSLs, 15 415 HPs, 120 TSAs) and 26 699 had conventional adenomas. High‐risk SSLs were enriched in the ascending colon (44.1% vs 2.6‐35.8% for other locations; P < .003). Early‐ and late‐onset SPs had similar subsite distribution. Early‐onset conventional adenomas were more enriched in the distal colon/rectum (51.8% vs 43.4%, P < .001). Multiple conventional adenomas were more represented in late‐onset groups (40.8% vs 33.8%, P < .001), with no difference in SSLs. The prevalence of conventional adenomas/high‐risk conventional adenomas increased continuously with age, whereas the prevalence of SSLs/high‐risk SSLs was stable from age 40 years onwards. A higher proportion of women were diagnosed with early‐onset than late‐onset SSLs (62.9% vs 57.6%, P = .03). Conventional adenomas, SSLs, early‐ and late‐onset polyps have distinct epidemiology. The findings have implications for improved colonoscopy screening and surveillance and understanding the etiologic heterogeneity of CRC.
What's new?
Precursor lesions to colorectal cancer (CRC) include serrated polyps (SPs), which account for nearly one‐third of colorectal malignancies. Nonetheless, epidemiological understanding and characterization of distinct SP subtypes remains limited. In our study, using data from the Partners Colonoscopy Cohort, the authors investigated demographic, endoscopic and histological features of SP subtypes. High‐risk sessile serrated lesions were found to be more common in women, in whom early‐onset lesions were more frequent, and to be highly enriched in the ascending colon. Prevalence of high‐risk sessile serrated lesions stabilized after age 40. The findings highlight the need for high‐quality screening colonoscopy in young adults.
Background and Aims
Conventional adenomas (CAs) and serrated polyps (SPs) are precursors to colorectal cancer (CRC). Understanding metachronous cancer risk is poor due to lack of accurate ...large-volume datasets. We outline the use of natural language processing (NLP) in forming the Partners Colonoscopy Cohort, an integrated longitudinal cohort of patients undergoing colonoscopies.
Methods
We identified endoscopy quality data from endoscopy reports for colonoscopies performed from 2007 to 2018 in a large integrated healthcare system, Mass General Brigham). Through modification of an established NLP pipeline, we extracted histopathological data (polyp location, histology and dysplasia) from corresponding pathology reports. Pathology and endoscopy data were merged by polyp location using a four-stage algorithm. NLP and merging procedures were validated by manual review of 500 pathology reports.
Results
305,656 colonoscopies in 213,924 patients were identified. After merging, 76,137 patients had matched polyp data for 334,750 polyps. CAs and SPs were present in 86,707 (28.5%) and 55,373 (18.2%) colonoscopies. Among patients with polyps at index screening colonoscopy, 14,931 (33.4%) had follow-up colonoscopy (median 46.4, interquartile range 33.8–62.4 months); 91 (0.2%) and 1127 (2.5%) patients developed metachronous CRC and high-risk polyps (polyps ≥ 10 mm or CAs having high-grade dysplasia/villous/tublovillous histology or SPs with dysplasia). Genetic data were available for 23,787 (31.7%) patients with polyps from the Partners Biobank. The validation study showed a positive predictive value of 100% for polyp histology and locations.
Conclusion
We created the Partners Colonoscopy Cohort providing essential infrastructure for future studies to better understand the natural history of CRC and improve screening and post-polypectomy strategies.
Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), ...fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio OR per 1 kg/m.sup.2 increase 1.01, 95% confidence interval CI 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk ...of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer.
Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia.
Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94).
This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.
Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations.
Two, one ...and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants.
Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (OR
, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (OR
1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined OR
was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer.
These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.
The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of ...the associations of RA with site-specific cancers in European and East Asian populations.
Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis.
In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval CI 1.03-1.10) for head and neck cancer, 1.06 (95% CI 1.02-1.10) for cervical cancer, 0.92 (95% CI 0.87-0.96) for testicular cancer, and 0.94 (95% CI 0.90-0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06-1.29) for pancreatic cancer, 0.91 (95% CI 0.88-0.94) for breast cancer, and 0.90 (95% CI 0.84-0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed.
This study suggests that RA may play a role in the development of several site-specific cancers.
Observational studies have shown that milk consumption is inversely associated with colorectal, bladder, and breast cancer risk, but positively associated with prostate cancer. However, whether the ...associations reflect causality remains debatable. We investigated the potential causal associations of milk consumption with the risk of colorectal, bladder, breast, and prostate cancer using a genetic variant near the LCT gene as proxy for milk consumption.
We obtained genetic association estimates for cancer from the UK Biobank (n = 367,643 women and men), FinnGen consortium (n = 135,638 women and men), Breast Cancer Association Consortium (n = 228,951 women), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254 men). Milk consumption was proxied by a genetic variant (rs4988235 or rs182549) upstream of the gene encoding lactase, which catalyzes the breakdown of lactose.
Genetically proxied milk consumption was associated with a reduced risk of colorectal cancer. The odds ratio (OR) for each additional milk intake increasing allele was 0.95 (95% confidence interval CI 0.91-0.99; P = 0.009). There was no overall association of genetically predicted milk consumption with bladder (OR 0.99; 95% CI 0.94-1.05; P = 0.836), breast (OR 1.01; 95% CI 1.00-1.02; P = 0.113), and prostate cancer (OR 1.01; 95% CI 0.99-1.02; P = 0.389), but a positive association with prostate cancer was observed in the FinnGen consortium (OR 1.07; 95% CI 1.01-1.13; P = 0.026).
Our findings strengthen the evidence for a protective role of milk consumption on colorectal cancer risk. There was no or limited evidence that milk consumption affects the risk of bladder, breast, and prostate cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from ...human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the
gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio OR per one standard deviation decrease in low-density lipoprotein LDL cholesterol 0.76, 95% confidence interval CI 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (
,
,
,
,
) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipid-lowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
Insulin‐like growth factor‐1 (IGF‐1) is involved in several processes relevant to carcinogenesis. We used 416 single‐nucleotide polymorphisms robustly associated with serum IGF‐1 levels to assess the ...potential causal associations between this hormone and site‐specific cancers through Mendelian randomization. Summary‐level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large‐scale consortia including individuals of European‐descent. Furthermore, we estimated genetic associations with 14 site‐specific cancers in European‐descent individuals in UK Biobank. Supplementary analyses were conducted for six site‐specific cancers using summary‐level data from the BioBank Japan Project. Genetically predicted serum IGF‐1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF‐1 levels was 1.11 (95% confidence interval CI 1.01‐1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09‐1.36; P = 3.9 × 10−4) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01‐1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97‐1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95‐1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92‐1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02‐1.13; P = 4.4 × 10−3) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF‐1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF‐1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF‐1 levels with prostate, breast, and other cancers.
This Mendelian randomization study found support for a causal association between elevated serum insulin‐like growth factor‐1 levels and increased risk of colorectal cancer.
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