Возраст-ассоциированный канцерогенез: Оценка риска и его эволюция

Association study between CYP24A1 gene polymorphisms and cancer risk

Transgender (TG) individuals have higher rates of mortality associated with cancer diagnoses, in part due to avoidance of gender-assigned cancer screenings resulting in later stages at diagnosis. Knowledge about the risks of breast or gynecological cancer in TG and nonbinary (NB) persons receiving gender-affirming hormone therapy is limited. Even less information exists regarding the subset of individuals with genetic predisposition for these malignancies. We performed a retrospective literature review of studies from the last 15years on breast cancer rates and identified risks in TG persons. An accumulating body of data on breast cancer incidence in TG persons suggests higher than previously believed rates of breast cancer in TG women compared with cisgender men and risk correlating with duration of hormone use. Few studies have examined other cancer risks in TG populations. To date, only three publications address the association with BRCA1/2 mutation presence and breast cancer incidence in TG persons. Meanwhile, there is growing awareness and social acceptance of TG/NB identities coupled with recognition of gender dysphoria at increasingly earlier ages. No information directly addressing cancer risk counseling in TG/NB adolescents and young adults with a family history of cancer or hereditary cancer syndrome exists. Whether the presence of a known genetic predisposition or strong family cancer history may affect cancer risk in these populations is unknown, leading to significant gaps in clinicians' ability to accurately and appropriately estimate cancer risks and counsel those with genetic predisposition on the risks/benefits associated with surgical options and the initiation, duration, and dosing of gender-affirming hormone therapies. A series of three cases illustrates the utility of cancer risk assessment and genetic testing in TG/NB adolescents and young adults, and the unique challenges and unanswered questions that are encountered in the process.

Most risk-based breast cancer prevention and screening strategies rely on estimated invasive breast cancer risk. A recently developed model from the Breast Cancer Surveillance Consortium (BCSC) identifies women at elevated advanced cancer risk (prognostic pathologic stage II or greater) despite undergoing regular mammography screening. To describe the characteristics of women identified for risk-based interventions based on advanced versus invasive breast cancer risk. Cross-sectional study. Women aged 40-74years undergoing mammography screening in routine clinical practice at 165 radiology facilities participating in the BCSC. Established BCSC risk models were used to calculate cumulative 6-year advanced breast cancer risk and BCSC 5-year invasive breast cancer risk, stratified by age, race and ethnicity, breast density, and body mass index. Among 756,971 included women, the Spearman correlation between advanced and invasive cancer risk scores was 0.75. 31.9% of women had intermediate/high (≥ 0.38%) advanced cancer risk and 32.5% had intermediate/high (≥ 1.67%) invasive cancer risk. 21.1% had intermediate/high risk in both models and 22.1% had intermediate/high risk in only one model. Thirty-five percent of women with intermediate/high invasive cancer risk had low/average advanced cancer risk, and 16% of women with low/average invasive cancer risk had intermediate/high advanced cancer risk. Among women with intermediate/high advanced cancer risk, 17.5% were age 40-49, 25.7% were Black, 69.7% had dense breasts, and 81.1% were overweight/obese. Among women with intermediate/high invasive breast cancer risk, 5.2% were age 40-49, 11.9% were Black, 56.5% had dense breasts, and 70.6% were overweight/obese. There are substantial differences in the characteristics of women identified as having elevated risk based on the advanced versus invasive breast cancer risk models. The advanced cancer risk model is important for identifying women who are young, Black, overweight/obese, or have dense breasts at intermediate/higher advanced cancer risk for consideration of risk-based interventions.

Objective: To study the associations between variants of mTORC1 of PI3K/AKT/mTOR pathway and colorectal cancer. Methods: In this hospital-based case-control study, at the First Affiliated Hospital, Xinjiang Medical University from 2000 to 2013, 665 primary colorectal cancer cases and 695 cancer-free controls were genotyped at 10 potentially functional single nucleotide polymorphism (SNPs) loci of mTORC1 (mTOR: rs1034528, rs2295080; Raptor: rs1062935, rs3751934; mLST8: rs3160, rs26865; DEPTOR: rs2271900, rs4871827; AKT1S1: rs2290774, rs2353005) to assess their associations with risk of colorectal cancer by Logistic regression analysis. Results: In single-locus analysis, found a significantly decreased risk of colorectal cancer associated with mLST8 rs26865 by recessive genetic model, especially in populations of ≤68 years of age (OR=0.64; 95%CI=0.43-0.96, P=0.031), female (OR=0.61; 95%CI=0.38-0.99, P=0.046), non-smoking (OR=0.55; 95%CI=0.35-0.87, P=0.010). mTOR rs1034528 CC genotypes were associated with higher risk of colorectal cancer in >68-year-old populations (OR=3.34; 95%CI=1.12-9.91, P=0.030). Raptor rs3751934 CA/AA genotypes were associated with lower colorectal cancer risk in population of body mass index(BMI)>25 kg/m(2) (OR=0.68; 95%CI=0.47-0.98, P=0.038); and AKT1S1 rs2290774 CC genotypes were associated with lower colorectal cancer risk in non-smoking population (OR=0.67; 95%CI=0.45-0.99, P=0.048). Furthermore, found that populations carrying more than two low-risk genotypes were associated with lower colorectal cancer risk, compared with that of populations carrying less than two low-risk genotypes (OR=0.74, 95%CI=0.58-0.95, P=0.017), especially in population of ≤68 years of age, male and BMI>25 kg/m(2,) and non-smoking. Conclusions: SNPs of mTORC1-related genes individually or jointly contribute to colorectal cancer susceptibility in Chinese. Further studies of larger cohorts are needed to validate the findings.

Colorectal cancer is the second most common cause of cancer deaths in the United States, and it disproportionally affects minority populations. Poor dietary habits, such as diet low in fruits and vegetables, increase the risk of colorectal cancer. Moreover, socioeconomic factors contribute to limited access to fresh and healthy foods and limited opportunities for safe physical activity, leading to poor physical health. In this interdisciplinary study, we aim to investigate any relationships between dietary behaviors and cancer risk in adults aged 50 years and above. We are recruiting participants at a senior center in East Harlem, New York City, a racially diverse and underserved community. The participants complete a NIH-validated survey through which we assess their dietary habits and collect standardized demographic data and history of cancer. Urine samples from participants are analyzed for polyphenols, commonly found in fruits and vegetables. Quantification of polyphenol content in urine is determined by a standard curve based on the concentration of gallic acid, a stable and convenient chemical that is representative of polyphenols from fruits and vegetables. So far, analysis of urine from a cohort of diverse participants (n=15) has been performed. The range of gallic acid concentration obtained was 3.85-17.14 μg/mL. We observed the lowest gallic acid concentration in a participant with history of cancer, suggesting low level of polyphenol content in their urine. Ongoing work includes further recruitment of participants and an intervention consisting of active nutritional education (cooking classes, workshops, etc.). A control group that will not receive this educational intervention will be provided with brochures through mail informing them about general health information. At the end of the intervention period, urine will be collected and analyzed to assess the impact of nutritional education on dietary habits in underserved and minority communities. Citation Format: Cristina N. Zambrano, Maayan Beeber, April Panitz, Yin Tan, Grace Ma, Khursheed Navder, Ming-Chin Yeh, Olorunseun Ogunwobi. Diet and risk of cancer in minority populations in New York City [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C047.

Previous studies have investigated the associations between FEN1 -69G>A (rs174538) and 4150G>T (rs4246215) polymorphisms and cancer risk in Chinese population. However, the results were controversial. We therefore carried out a meta-analysis to derive a more precise estimation of the associations. PubMed Database was systematically searched to identify potentially eligible literatures. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of associations between FEN1 -69G>A and 4150G>T polymorphisms and cancer risk in Chinese population. A total of 4 articles, including 5,108 cases and 6,382 controls, were used to evaluate the effect of the two polymorphisms on cancer risk. The pooled ORs indicated that FEN1 -69G>A and 4150G>T polymorphisms were significantly associated with cancer risk in Chinese population. In stratified analyses by cancer type, significant associations were also observed in digestive system cancer. In addition, haplotypes consisting of -69G>A and 4150G>T polymorphisms were closely associated with cancer risk. Interestingly, significantly correlation between FEN1 -69G>A polymorphism and mRNA expression was observed. In conclusion, this meta-analysis suggests that FEN1 -69G>A and 4150G>T polymorphisms may be associated with cancer susceptibility in Chinese population. However, further investigation on large population and different ethnicities are warranted.

Background and Objective: Cyclins are the key regulator of the cell cycle and their over-expression has been seen in many cancers including breast cancer. Cyclin D1 is an oncoprotein encoded by CCND1 gene located on chromosome 11 (11q) which regulates cell cycle in shifting from G1 to S phase. It’s the main target for steroids and mitogenic growth hormones in breast epithelial cells. This study aimed to evaluate the relationship between Cyclin D1 G870A polymorphism and breast cancer risk in a population in the north of Iran.
 Methods: Whole blood samples collected from 82 patients with breast cancer and 66 healthy women. DNA was extracted and genotyping was performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) technique.
 Results: Genotypic prevalence of AA, AG, GG genotypes among patients were 40.2%, 35.3% and 24.4% and in controls were 30%, 47%, 23%, respectively. There was no significant difference in CCND1 G870A genotype polymorphism between patients and control group (p=0.32). Also, allelic prevalence of A and G alleles in breast cancer patients were 58% and 42%, in controls were 54% and 46%, respectively. The present study showed that there is no significant association between CCND1 G870A polymorphism with the risk of breast cancer.
 Conclusion: The results of this study revealed that there is no significant association between CCND1 G870A genetic polymorphism and the risk of breast cancer in the population of the north of Iran. More studies with larger samples of cases and controls would be beneficial.

Breast cancer is the most common cancer for women around the world. The presence of single nucleotide polymorphisms (SNP) on or near the coding region of breast cancer susceptibility genes can affect the regulation of gene expression, which may increase or decrease the risk of breast cancer. BARX2 was showed to stimulate the expression of ERS1, which involved in the development of breast cancer. SNP rs7107217 on 152kb downstream of the BARX2 could affect the level of protein BARX2 and had been proved to associate with the breast cancer risk in populations similar to Vietnamese, including Chinese and Korean. In this study, rs7107217 was genotyped and initially detemined the association with the breast cancer risk in Vietnamese. Real-time PCR HRM was optimized and used to genotype rs7107217 in 117 breast cancer cases and 105 healthy controls. Thereafter, the correlation of this SNP with the risk of breast cancer was initially determined by analyzing the differences in allelic and genotypic frequencies between cases and control groups. The results showed the optimal rs7107217 genotyping condition was successfully developed with the high sensitivity, specificity, and consistency. SNP rs7107217 had high polymorphism with the frequency of minor allele C of 29.9% and 35.3% in case and control, respectively. SNP rs7107217 had been found no association with the breast cancer risk (C vs A: P = 0.23, OR (95% CI) = 0.79 (0.53 – 1.17)). However with the low reliability of the analysis (11.71%) and the high potential related to the formation of breast cancer, the association between rs7107217 and breast cancer risk in Vietnamese population should be further conducted on a larger sample size to get higher accuracy.

385P - Identifying CASP8 polymorphisms associated with breast cancer risk in an Iranian population

BackgroundLung cancer is the leading cause of cancer death globally. Recent studies have revealed that CYP19A1 gene plays a crucial role in cancer initiation and development. The aim of this study was to assess the association of CYP19A1 genetic polymorphisms with the risk of lung cancer in the Chinese Han population.MethodsThis study randomly recruited 489 lung cancer patients and 467 healthy controls. The genotypes of four single nucleotide polymorphisms (SNPs) of the CYP19A1 gene were identified by the Agena MassARRY technique. Genetic model analysis was used to assess the association between genetic variations and lung cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the effect of four selected SNPs on lung cancer risk.ResultsCYP19A1 rs28757157 might contribute to an increased risk of lung cancer (p = 0.025, OR = 1.30, 95% CI 1.03–1.64). In stratified analysis, rs28757157 was associated with an increased cancer risk in the population aged under 60 years, females, smokers, and drinkers. Besides, rs3751592 and rs59429575 were also identified as risk biomarkers in the population under 60 years and drinkers. Meanwhile, a relationship between an enhanced risk of squamous cell carcinoma and rs28757157 was found, while the rs3751592 CC genotype was identified as a risk factor for lung adenocarcinoma development.ConclusionsThis study has identified revealed that the three SNPs (rs28757157, rs3751592, and rs59429575) of CYP19A1 are associated with lung cancer in the Chinese Han population. These findings will provide theoretical support for further functional studies of CYP19A1 in lung cancer.

Many molecular epidemiological studies have been performed to explore the association between MTHFR C677T polymorphism and cancer risk in diverse populations. However, the results were inconsistent. Hence, we performed a meta-analysis to investigate the association between cancer risk and MTHFR C677T (150,086 cases and 200,699 controls from 446 studies) polymorphism. Overall, significantly increased cancer risk was found when all eligible studies were pooled into the meta-analysis. In the further stratified and sensitivity analyses, significantly increased breast cancer risk was found in Asians and Indians, significantly decreased colon cancer risk was found, significantly decreased colorectal cancer risk was found in male population, significantly increased gastric cancer risk was found in Caucasians and Asians, significantly increased hepatocellular cancer risk was found in Asians, significantly decreased adult acute lymphoblastic leukemia (AALL) risk was found in Caucasians, significantly decreased childhood acute lymphoblastic leukemia (CALL) risk was found in Asians, and significantly increased multiple myeloma and NHL risk was found in Caucasians. In summary, this meta-analysis suggests that MTHFR C677T polymorphism is associated with increased breast cancer, gastric cancer, and hepatocellular cancer risk in Asians, is associated with increased gastric cancer, multiple myeloma, and NHL risk in Caucasians, is associated with decreased AALL risk in Caucasians, is associated with decreased CALL risk in Asians, is associated with increased breast cancer risk in Asians, is associated with decreased colon cancer risk, and is associated with decreased colorectal cancer risk in male population. Moreover, this meta-analysis also points out the importance of new studies, such as Asians of HNC, Asians of lung cancer, and Indians of breast cancer, because they had high heterogeneity in this meta-analysis (I(2) > 75%).

Previous studies have investigated the association between osteopontin (OPN) gene polymorphisms, rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) and cancer risk in the Chinese population. However, the results are controversial and indefinite. We therefore carried out a meta-analysis to derive a more precise estimation of these associations. The PubMed database was systematically searched to identify potentially eligible reports. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations between 3 OPN gene polymorphisms and cancer risk in a Chinese population. A total of 10 articles involving 2,391 cases and 3,007 controls were evaluated. The pooled OR indicated that OPN rs17524488 (−156 GG/G) polymorphism was significantly associated with cancer risk in Chinese population. In a stratified analysis by source of control, significant associations were also observed among rs17524488 (−156 GG/G) and rs11730582 (−443 T/C) polymorphisms and cancer. In addition, a stronger association was observed between rs9138 (C/A) polymorphism and cancer risk. In conclusion, this meta-analysis suggests that OPN rs17524488 (−156 GG/G), rs11730582 (−443 T/C), and rs9138 (C/A) polymorphisms may be associated with cancer susceptibility in the Chinese population. Nevertheless, further investigation on a larger population covering different ethnicities are warranted.

We read with great interest the paper titled “X-ray repair crosscomplementing group 1 Arg194Trp polymorphism is associated with increased risk of lung cancer in Chinese Han population” published in Tumor Biol. 2013, 34: 2611–2615 [1].Wu et al. performed a meta-analysis to investigate the association between X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp polymorphism and lung cancer risk in Chinese Han population on the basis of 12 case-control studies with 4385 cases and 4545 controls. The authors found that XRCC1 Arg194Trp polymorphism was associated with increased risk of lung cancer in Chinese Han population under three main models (allele contrast model, odds ratio (OR)=1.12, 95 % confidence interval (CI) 1.00–1.26, P=0.049; homozygote model, OR=1.27, 95 % CI 1.09–1.48, P=0.003; recessive model, OR=1.26, 95 % CI 1.09–1.46, P=0.003) when all eligible studies were pooled into meta-analysis. It is an interesting study. Nevertheless, a careful examination of the data provided by Wu et al. (Fig. 1 in the original text) [1] revealed two key issues that are worth noticing. Firstly, one overlapping paper [2] was not properly excluded from Wu et al.’s study [1]. Secondly, four eligible papers [3–6] published before 2013 were not included in Wu et al.’s study [1]. Therefore, the conclusions by Wu et al. [1] are not entirely reliable. In order to obtain a precise estimation of the relationship between XRCC1 Arg194Trp polymorphism and lung cancer risk in Chinese population, a meta-analysis was re-conducted on the basis of a total of 16 studies with 4591 cases and 4899 controls, which may provide comprehensive evidence for the association of XRCC1 Arg194Trp polymorphism with lung cancer risk in Chinese population. Table 1 listed the general information of selected studies. Table 2 listed the summary odds ratios of the association between XRCC1 Arg194Trp polymorphism and lung cancer risk in Chinese population. Overall, we observed an increased lung cancer risk in Chinese population among subjects carrying XRCC1 194 Trp/Trp genotype (OR=1.26, 95 % CI 1.09–1.46) comparing with Arg/ Arg genotype carriers in total population (Fig. 1a). We did not observe any association of Arg/Trp vs. Arg/Arg and Trp/Trp+Arg/Trp vs. Arg/Arg polymorphisms with lung cancer risk in Chinese population (OR=1.05, 95 % CI 0.90–1.22 and OR=1.12, 95 % CI 0.95–1.31, respectively) (Fig. 1b, c). In the subgroup analysis by a source of control, we observed an increased risk of XRCC1 194 Trp/Trp vs. Arg/Arg polymorphism for lung cancer in a healthy subject-based study (OR=1.34, 95 % CI 1.13– 1.59) (Table 2); we did not observe any association between XRCC1 Arg194Trp polymorphism and lung cancer risk in additional subgroup analyses (Table 2). Limiting H. Yang Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou 450001, People’s Republic of China

Background: Cancer and diabetes are common conditions that exert serious effect on public health in the United States. Their co-diagnosis in the same individual is not uncommon. Both conditions are seen to share risk factors such as obesity and sedentary lifestyle. Despite the extensive body of literature on the risk of cancer in individuals with diabetes, only a few have examined the pattern of cancer risk during different study time window following diabetes onset. To this end, there is a need to access the association between T2DM duration and the risk of breast cancer in order to accurately provide more effective interventions. Objective: To identify the risk of breast cancer associated with patients diagnosed with Type 2 diabetes mellitus (T2DM). An additional objective of this study is to examine the risk of breast cancer in individuals with incident type 2 diabetes during different time windows following T2DM onset. Also to evaluate any potential ascertainment or surveillance bias around the time of T2DM diagnosis compared to patients without diabetes. Methods: A retrospective cohort study was conducted on female participants (n= 2,318,205) utilizing the general practitioner research database (GPRD) to assess the incidence of breast cancer events in T2DM patients. The comparison group was patients without diabetes. The study period was 1 January 2003 to 31 December 2010. Results: A total of 118,174 patients with T2DM and 2,200,031 patients without diabetes were identified. Patients with T2DM were 2 times more likely to have breast cancer compared to patients without diabetes (1.792 [1.708, 1.880]). After adjustment for identified risk factors, age, BMI, alcohol, tobacco and estrogen use and Charlson Comorbidity Index (CCI), patients with T2DM were still at an increased risk (HR: 1.108 95% CI 1.053 -- 1.166). This association was still observed when cohort was categorized into a younger (<55) and an older age group (55+) in order to account for menopausal status. Examining breast cancer risk by duration of diabetes did not indicate a potential for detection bias. Conclusions: Women with T2DM may have a slightly increased risk of breast cancer and are seen to present with higher comorbid conditions. There was no suggestion of detection bias.

Background: Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences. This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies.Methods: PubMed, Embase, Scopus, and ScienceDirect databases were searched until 9 April 2018 to identify eligible studies. Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI). Studies that met the following criteria were excluded: review articles, meta-analysis, abstracts or conference papers; duplicate publications; studies on animals or cell-lines; studies without a case-control design; studies that did not report genotype frequencies. Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832. Stratified analysis according to quality scores, genotyping method, ethnicity, broad cancer category and cancer type was also performed.Results: Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population. The association was only significant in Asians but not Caucasians. In subgroup analysis, significant associations were found in high quality studies, gynecological cancers, ovarian, breast, and hepatocellular cancer. Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians. However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model.Conclusions: The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians. Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer. This study had some limitations such as significant heterogeneity in most contrasts, limited number of studies enrolling Africans or Caucasians ancestry and lack of adjustment for covariates and environmental interactions.