Circulating miRNAs signature on breast cancer: the MCC-Spain project.

PURPOSE: To build models combining circulating microRNAs (miRNAs) able to identify women with breast cancer as well as different types of breast cancer, when comparing with controls without breast cancer. METHOD: miRNAs analysis was performed in two phases: screening phase, with a total n = 40 (10 controls and 30 BC cases) analyzed by Next Generation Sequencing, and validation phase, which included 131 controls and 269 cases. For this second phase, the miRNAs were selected combining the screening phase results and a revision of the literature. They were quantified using RT-PCR. Models were built using logistic regression with LASSO penalization. RESULTS: The model for all cases included seven miRNAs (miR-423-3p, miR-139-5p, miR-324-5p, miR-1299, miR-101-3p, miR-186-5p and miR-29a-3p); which had an area under the ROC curve of 0.73. The model for cases diagnosed via screening only took in one miRNA (miR-101-3p); the area under the ROC curve was 0.63. The model for disease-free cases in the follow-up had five miRNAs (miR-101-3p, miR-186-5p, miR-423-3p, miR-142-3p and miR-1299) and the area under the ROC curve was 0.73. Finally, the model for cases with active disease in the follow-up contained six miRNAs (miR-101-3p, miR-423-3p, miR-139-5p, miR-1307-3p, miR-331-3p and miR-21-3p) and its area under the ROC curve was 0.82. CONCLUSION: We present four models involving eleven miRNAs to differentiate healthy controls from different types of BC cases. Our models scarcely overlap with those previously reported.

Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase-control study (MCC-Spain).

Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (

Effect of the use of prediagnosis hormones on breast cancer prognosis: MCC-Spain study.

OBJECTIVE: To extend knowledge about the long-term use of hormones in hormone therapy or oral contraception as prognostic factors in breast cancer. METHODS: The MCC-Spain project is a cohort of 1,685 women with incident breast cancer recruited in Spain. Recruitment was carried out between 2007 and 2010, and the follow-up finished in December 2017. The impact of hormone therapy or oral contraception on breast cancer prognosis was analyzed considering year of birth and menopausal status (1,095 women [65%] were postmenopausal). Hazard ratios (HRs) were estimated using Cox regression models. Death by any cause was considered as the event, and hormone therapy or oral contraception were analyzed as regressors. RESULTS: Oral contraception use for less than 5 years shows an HR of 1.10 (95% CI, 0.75 to 1.62), whereas use for 5 or more years shows an HR of 1.46 (95% CI, 0.95 to 2.25), with a P trend of 0.01, showing a dose-dependent response. Regarding hormone therapy and restricting the analysis to postmenopausal women born between1940 and 1959, where most hormone therapy (consumption) is concentrated, the results did not show any trend. CONCLUSION: Concerning oral contraception use, our results demonstrate that their use is related to poor prognosis in breast cancer. However, research in this field is limited and controversial, indicating the need for more research in this area. Regarding hormone therapy consumption, our results indicate no association with better prognosis, which contradicts what has previously been published.

Toenail zinc as a biomarker: Relationship with sources of environmental exposure and with genetic variability in MCC-Spain study.

BACKGROUND: Toenails are commonly used as biomarkers of exposure to zinc (Zn), but there is scarce information about their relationship with sources of exposure to Zn. OBJECTIVES: To investigate the main determinants of toenail Zn, including selected sources of environmental exposure to Zn and individual genetic variability in Zn metabolism. METHODS: We determined toenail Zn by inductively coupled plasma mass spectrometry in 3,448 general population controls from the MultiCase-Control study MCC-Spain. We assessed dietary and supplement Zn intake using food frequency questionnaires, residential proximity to Zn-emitting industries and residential topsoil Zn levels through interpolation methods. We constructed a polygenic score of genetic variability based on 81 single nucleotide polymorphisms in genes involved in Zn metabolism. Geometric mean ratios of toenail Zn across categories of each determinant were estimated from multivariate linear regression models on log-transformed toenail Zn. RESULTS: Geometric mean toenail Zn was 104.1 µg/g in men and 100.3 µg/g in women. Geometric mean toenail Zn levels were 7 % lower (95 % confidence interval 1-13 %) in men older than 69 years and those in the upper tertile of fibre intake, and 9 % higher (3-16 %) in smoking men. Women residing within 3 km from Zn-emitting industries had 4 % higher geometric mean toenail Zn levels (0-9 %). Dietary Zn intake and polygenic score were unrelated to toenail Zn. Overall, the available determinants only explained 9.3 % of toenail Zn variability in men and 4.8 % in women. DISCUSSION: Sociodemographic factors, lifestyle, diet, and environmental exposure explained little of the individual variability of toenail Zn in the study population. The available genetic variants related to Zn metabolism were not associated with toenail Zn.

[Family history of first degree as a risk factor for colorectal cancer]. / Antecedentes familiares de primer grado como factor de riesgo en el cáncer colorrectal.

OBJECTIVE: To evaluate the association between first-degree family history and colorectal cancer (CRC). METHOD: We analyzed data from 2857 controls and 1360 CRC cases, collected in the MCC-Spain project. The adjusted odds ratio (OR) and 95% confidence interval (95% CI) of association with the family history of CRC was estimated by non-conditional logistic regression. RESULTS: First-degree relatives doubled the risk of CRC (OR: 2.19; 95% CI: 1.80-2.66), increasing in those with two or more (OR: 4.22; 95% CI: 2.29-7.78) and in those whose relatives were diagnosed before 50 years (OR: 3.24; 95% CI: 1.52-6.91). Regarding the association of the family history with the location, no significant differences were observed between colon and rectum, but there were in the relation of these with the age of diagnosis, having more relatives those diagnosed before 50 years (OR: 4.79; 95% CI: 2.65-8.65). CONCLUSIONS: First-degree relatives of CRC increase the chances of developing this tumor, they also increase when the relative is diagnosed at an early age. Therefore, it must be a target population on which to carry out prevention measures.

[Discrimination and its relationship with risk behaviors and perceived health in spanish university students: a cross-sectional study.] / Discriminación y su relación con las conductas de riesgo y la salud percibida en estudiantes universitarios españoles: un estudio transversal.

OBJECTIVE: Discrimination during vital moments, such as the university period, can generate a high impact on people's behavior and health. The aim of this study was to analyze the possible association of discrimination with perceived health and with different risk behaviors, as well as to describe gender differences in Spanish university students. Discrimination during vital moments, such as college, can have a high impact on people's behavior and health. METHODS: A cross-sectional study was carried out with data from first-year university students from 11 Spanish universities (n=9,862). Discrimination, perceived health, alcohol consumption, smoking, consumption of illegal substances, leisure time connected to the Internet, risky sexual relations, family function, risk of mental health problems and risk of eating disorders were assessed. Prevalences with their 95% confidence intervals were obtained and for quantitative variables the mean and standard deviation were calculated. Odds ratios with 95% confidence intervals were calculated to determine the relationship between discrimination and the other variables. RESULTS: An association was found between discrimination and fair or poor perceived health (OR: 1.7; p=0.0001), consumption of illegal substances (OR: 1.3; p=0.002), problematic internet use (OR: 1.3; p=0.004), family dysfunction (OR: 1.8; p=0.0001), risk of mental health problems (OR: 1.9; p=0.0001) and eating disorders (OR: 1.5; p=0.0001). Regarding gender differences, higher prevalence of discrimination was observed in men with health status perceived as fair or worse (OR: 2.2; p=0.0001), family dysfunction (OR: 1.8; p=0.0001), risk of mental health problems (OR: 2.2; p=0.0001) and eating disorders (OR: 1.9; p=0.002). Women, apart from the previous variables, presented association of discrimination with consumption of illegal substances (OR: 1.3; p=0.005) and problematic internet use (OR: 1.4; p=0.002). CONCLUSIONS: The study findings underline that there is an association between discrimination and risk behaviors among Spanish university students. In turn, discrimination was associated with poor or fair perceived health, this relationship being similar in both men and women.

OBJETIVO: La discriminación durante los momentos vitales, como el periodo universitario, puede generar un alto impacto en la conducta y en el estado de salud de las personas. El estudio tuvo como objetivo analizar la posible asociación de la discriminación con la salud percibida y con distintas conductas de riesgo, así como describir las diferencias de género en estudiantes universitarios españoles. METODOS: Se realizó un estudio transversal con datos de estudiantes universitarios de primera matrícula de primer curso de 11 universidades españolas (n=9.862). Se valoró la discriminación, la salud percibida, el consumo de alcohol, el hábito tabáquico, el consumo de sustancias ilegales, el tiempo de ocio conectado a internet, la práctica de relaciones sexuales de riesgo, la función familiar, el riesgo de problemas de salud mental y el riesgo de trastornos de la conducta alimentaria. Se obtuvieron las prevalencias con sus intervalos de confianza al 95% y para las variables cuantitativas la media y desviación estándar. Se calcularon las Odds Ratio con los intervalos de confianza al 95% para conocer la relación entre la discriminación y las otras variables. RESULTADOS: Se encontró asociación entre la discriminación y una regular o mala salud percibida (OR: 1,7; p=0,0001), el consumo de sustancias ilegales (OR: 1,3; p=0,002), el uso problemático de internet (OR: 1,3; p=0,004), la disfunción familiar (OR: 1,8; p=0,0001), el riesgo de problemas de salud mental (OR: 1,9; p=0,0001) y de trastornos de la conducta alimentaria (OR: 1,5; p=0,0001). En cuanto a las diferencias de género, se apreciaron mayores prevalencias de discriminación en hombres con estado de salud percibida como regular o peor (OR: 2,2; p=0,0001), disfunción familiar (OR: 1,8; p=0,0001), riesgo de problemas de salud mental (OR: 2,2; p=0,0001) y de trastornos de la conducta alimentaria (OR: 1,9; p=0,002). Las mujeres, además de las variables anteriores, mostraron asociación de la discriminación con el consumo de sustancias ilegales (OR: 1,3; p=0,005) y el uso problemático de internet (OR: 1,4; p=0,002). CONCLUSIONES: Los hallazgos del estudio subrayan que existe asociación entre la discriminación y las conductas de riesgo de los estudiantes universitarios españoles. A su vez, la discriminación se asoció con una mala o regular salud percibida, siendo esta relación similar tanto en hombres como en mujeres.

Adequacy of early-stage breast cancer systemic adjuvant treatment to Saint Gallen-2013 statement: the MCC-Spain study.

The St Gallen Conference endorsed in 2013 a series of recommendations on early breast cancer treatment. The main purpose of this article is to ascertain the clinical factors associated with St Gallen-2013 recommendations accomplishment. A cohort of 1152 breast cancer cases diagnosed with pathological stage < 3 in Spain between 2008 and 2013 was begun and then followed-up until 2017/2018. Data on patient and tumour characteristics were obtained from medical records, as well as their first line treatment. First line treatments were classified in three categories, according on whether they included the main St Gallen-2013 recommendations, more than those recommended or less than those recommended. Multinomial logistic regression models were carried out to identify factors associated with this classification and Weibull regression models were used to find out the relationship between this classification and survival. About half of the patients were treated according to St Gallen recommendations; 21% were treated over what was recommended and 33% received less treatment than recommended. Factors associated with treatment over the recommendations were stage II (relative risk ratio [RRR] = 4.2, 2.9-5.9), cancer positive to either progesterone (RRR = 8.1, 4.4-14.9) or oestrogen receptors (RRR = 5.7, 3.0-11.0). Instead, factors associated with lower probability of treatment over the recommendations were age (RRR = 0.7 each 10 years, 0.6-0.8), poor differentiation (RRR = 0.09, 0.04-0.19), HER2 positive (RRR = 0.46, 0.26-0.81) and triple negative cancer (RRR = 0.03, 0.01-0.11). Patients treated less than what was recommended in St Gallen had cancers in stage 0 (RRR = 21.6, 7.2-64.5), poorly differentiated (RRR = 1.9, 1.2-2.9), HER2 positive (RRR = 3.4, 2.4-4.9) and luminal B-like subtype (RRR = 3.6, 2.6-5.1). Women over 65 years old had a higher probability of being treated less than what was recommended if they had luminal B-like, HER2 or triple negative cancer. Treatment over St Gallen was associated with younger women and less severe cancers, while treatment under St Gallen was associated with older women, more severe cancers and cancers expressing HER2 receptors.

Dietary Constituents: Relationship with Breast Cancer Prognostic (MCC-SPAIN Follow-Up).

The aim of this study was to characterize the relationship between the intake of the major nutrients and prognosis in breast cancer. A cohort based on 1350 women with invasive (stage I-IV) breast cancer (BC) was followed up. Information about their dietary habits before diagnosis was collected using a semi-quantitative Food Frequency Questionnaire. Participants without FFQ or with implausible energy intake were excluded. The total amount consumed of each nutrient (Kcal/day) was divided into tertiles, considering as "high intakes" those above third tertile. The main effect studied was overall survival. Cox regression was used to assess the association between death and nutrient intake. During a median follow-up of 6.5 years, 171 deaths were observed. None of the nutrients analysed was associated with mortality in the whole sample. However, in normal-weight women (BMI 18.5-25 kg/m2) a high intake of carbohydrates (≥809 Kcal/day), specifically monosaccharides (≥468 Kcal/day), worsened prognostic compared to lowest (≤352 Kcal/day). Hazard Ratios (HRs) for increasing tertiles of intake were HR:2.22 95% CI (1.04 to 4.72) and HR:2.59 95% CI (1.04 to 6.48), respectively (p trend = 0.04)). Conversely, high intakes of polyunsaturated fats (≥135 Kcal/day) improved global survival (HR: 0.39 95% CI (0.15 to 1.02) p-trend = 0.05) compared to the lowest (≤92.8 kcal/day). In addition, a protective effect was found substituting 100 kcal of carbohydrates with 100 kcal of fats in normal-weight women (HR: 0.76 95% CI (0.59 to 0.98)). Likewise, in premenopausal women a high intake of fats (≥811 Kcal/day) showed a protective effect (HR:0.20 95% CI (0.04 to 0.98) p trend = 0.06). Finally, in Estrogen Receptors (ER) negative tumors, we found a protective effect of high intake of animal proteins (≥238 Kcal/day, HR: 0.24 95% CI (0.06 to 0.98). According to our results, menopausal status, BMI and ER status could play a role in the relationship between diet and BC survival and must be taken into account when studying the influence of different nutrients.

Quality of Life in a Cohort of 1078 Women Diagnosed with Breast Cancer in Spain: 7-Year Follow-Up Results in the MCC-Spain Study.

Breast cancer is the most frequent cause of tumors and net survival is increasing. Achieving a higher survival probability reinforces the importance of studying health-related quality of life (HR-QoL). The main aim of this work is to test the relationship between different sociodemographic, clinical and tumor-intrinsic characteristics, and treatment received with HR-QoL measured using SF-12 and the FACT/NCCN (National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy) Breast Symptom Index (FBSI). Women with breast cancer recruited between 2008 and 2013 and followed-up until 2017-2018 in a prospective cohort answered two HR-QoL surveys: the SF-12 and FBSI. The scores obtained were related to woman and tumor characteristics using linear regression models. The telephone survey was answered by 1078 women out of 1685 with medical record follow-up (64%). Increases in all three HR-QoL scores were associated with higher educational level. The score differences between women with university qualifications and women with no schooling were 5.43 for PCS-12, 6.13 for MCS-12 and 4.29 for FBSI. Histological grade at diagnosis and recurrence in the follow-up displayed a significant association with mental and physical HR-QoL, respectively. First-line treatment received was not associated with HR-QoL scores. On the other hand, most tumor characteristics were not associated with HR-QoL. As breast cancer survival is improving, further studies are needed to ascertain if these differences still hold in the long run.

Tumour characteristics and survivorship in a cohort of breast cancer: the MCC-Spain study.

PURPOSE: The objective of this study is to analyse the relative survival with breast cancer in women diagnosed after new treatments were generalised and to ascertain the current effect that tumour characteristics such as grade, stage or subtype have on survival as well as the new AJCC-pathological prognostic score. METHODS: The breast cancer MCC-Spain follow-up study is a prospective cohort study of 1685 incident breast cancer cases. Women between 20 and 85 years old were recruited between the years 2008 and 2013 in 18 hospitals located in 10 Spanish provinces and they have been followed until 2017/2018. Relative survival was estimated after 3, 5 and 8 years of follow-up using Ederer II method. In addition, Weibull regression adjusted by age, hospital, grade and stage was used to investigate prognosis factors. RESULTS: Among components of TNM staging system, tumour size greater than 50 mm (i.e. T3 or T4) more than doubled the risk of dying, while N3 nodal involvement and presence of metastasis had a huge effect on mortality. The AJCC pathological prognostic score strongly correlated with survival; thus, hazard ratios increased as the score rose, being 2.31, 4.00, 4.94, 7.92, 2.26, 14.9 and 58.9 for scores IB, IIA, IIB, IIIA, IIIB, IIIC and IV, respectively. CONCLUSION: Both TNM staging and histological/molecular biomarkers are associated with overall survival in Spanish women with breast cancer; when both are combined in the AJCC pathological prognosis score, the prognostic value improved with risk indices that increased rapidly as the pathological prognosis score increased.

Author Correction: Validating a breast cancer score in Spanish women. The MCC-Spain study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fatty acid intake and breast cancer in the Spanish multicase-control study on cancer (MCC-Spain).

PURPOSE: To evaluate the association between dietary fat and fat subtype and breast cancer development. METHODS: We conducted a case-control study with 1181 cases of incident breast cancer, diagnosed between 2007 and 2012, and 1682 population controls frequency matched (by age, sex, and region) from the Spanish multicenter case-control study MCC-Spain. RESULTS: We found a significant protective effect in premenopausal women of total fat intake [OR 0.51 95% CI (0.31-0.86) highest versus lowest tertile], but no effect was observed in menopausal women [OR 1.15 95% CI (0.83-1.60)]. Analyzing by type of fat, this protective effect persisted only for the monounsaturated fatty acids [OR 0.51 95% CI (0.32-0.82)]. In contrast, other fatty acids did not have a significant effect. In addition, a protection against risk of breast cancer was found when polyunsaturated fats were "substituted" by monounsaturated, maintaining the same total fat intake [OR 0.68 95% CI (0.47-0.99)]. Finally, analyzing by breast cancer subtype, we found no effect, except in premenopausal women where intake of moderate [OR 0.52 95% CI (0.33-0.82)] and high monounsaturated fatty acids [OR 0.47 95% CI (0.27-0.82)] maintains a protective effect against ER/PR + tumors. In contrast, in menopausal women, a high intake of monounsaturated fatty acids was associated with higher risk of HER2 + tumors [OR 2.00 95% CI (0.97-4.13)]. CONCLUSION: Our study shows a differential effect of monounsaturated fatty acids according to menopausal status and breast cancer subtype.

Cohort profile: the MCC-Spain follow-up on colorectal, breast and prostate cancers: study design and initial results.

PURPOSE: Since 2016, the multicase-control study in Spain (MCC-Spain) has focused towards the identification of factors associated with cancer prognosis. Inception cohorts of patients with colorectal, breast and prostate cancers were assembled using the incident cases originally recruited. PARTICIPANTS: 2140 new cases of colorectal cancer, 1732 of breast cancer and 1112 of prostate cancer were initially recruited in 12 Spanish provinces; all cancers were incident and pathologically confirmed. Follow-up was obtained for 2097 (98%), 1685 (97%) and 1055 (94.9%) patients, respectively. FINDINGS TO DATE: Information gathered at recruitment included sociodemographic factors, medical history, lifestyle and environmental exposures. Biological samples were obtained, and 80% of patients were genotyped using a commercial exome array. The follow-up was performed by (1) reviewing medical records; (2) interviewing the patients by phone on quality of life; and (3) verifying vital status and cause of death in the Spanish National Death Index. Ninety-seven per cent of recruited patients were successfully followed up in 2017 or 2018; patient-years of follow-up were 30 914. Most colorectal cancers (52%) were at clinical stage II or lower at recruitment; 819 patients died in the follow-up and the 5-year survival was better for women (74.4%) than men (70.0%). 71% of breast cancers were diagnosed at stages I or II; 206 women with breast cancer died in the follow-up and the 5-year survival was 90.7%. 49% of prostate cancers were diagnosed at stage II and 32% at stage III; 119 patients with prostate cancer died in the follow-up and the 5-year survival was 93.7%. FUTURE PLANS: MCC-Spain has built three prospective cohorts on highly frequent cancers across Spain, allowing to investigate socioeconomic, clinical, lifestyle, environmental and genetic variables as putative prognosis factors determining survival of patients of the three cancers and the inter-relationship of these factors.

Epidemiology of non-steroidal anti-inflammatory drugs consumption in Spain. The MCC-Spain study.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used despite their risk of gastrointestinal bleeding or cardiovascular events. We report the profile of people taking NSAIDs in Spain, and we include demographic factors, health-related behaviours and cardiovascular disease history. METHODS: Four thousand sixtyparticipants were selected using a pseudorandom number list from Family Practice lists in 12 Spanish provinces. They completed a face-to-face computerized interview on their NSAID consumption, demographic characteristics, body mass index, alcohol and tobacco consumption and medical history. In addition, participants completed a self-administered food-frequency and alcohol consumption questionnaire. Factors associated with ever and current NSAID consumption were identified by logistic regression. RESULTS: Women consumed more non-aspirin NSAIDs (38.8% [36.7-41.0]) than men (22.3 [20.5-24.2]), but men consumed more aspirin (11.7% [10.3-13.2]) than women (5.2% [4.3-6.3]). Consumption of non-aspirin NSAIDs decrease with age from 44.2% (39.4-49.1) in younger than 45 to 21.1% (18.3-24.2) in older than 75, but the age-pattern for aspirin usage was the opposite. Aspirin was reported by about 11% patients, as being twice as used in men (11.7%) than in women (5.2%); its consumption increased with age from 1.7% (< 45 years old) to 12.4% (≥75 years old). Aspirin was strongly associated with the presence of cardiovascular risk factors or established cardiovascular disease, reaching odds ratios of 15.2 (7.4-31.2) in women with acute coronary syndrome, 13.3 (6.2-28.3) in women with strokes and 11.1 (7.8-15.9) in men with acute coronary syndrome. Participants with cardiovascular risk factors or diseases consumed as much non-aspirin NSAID as participants without such conditions. CONCLUSIONS: Non-aspirin NSAIDs were more consumed by women and aspirin by men. The age patterns of aspirin and non-aspirin NSAIDs were opposite: the higher the age, the lower the non-aspirin NSAIDs usage and the higher the aspirin consumption. People with cardiovascular risk factors or diseases consumed more aspirin, but they did not decrease their non-aspirin NSAIDs usage.

Pigmentation phototype and prostate and breast cancer in a select Spanish population-A Mendelian randomization analysis in the MCC-Spain study.

INTRODUCTION: Phototype has been associated with an increased risk of prostate cancer, and it is yet unknown if it is related to other hormone-dependent cancers, such as breast cancer or whether this association could be considered causal. METHODS: We examined the association between the phototype and breast and prostate cancers using a Mendelian randomization analysis. We studied 1,738 incident cases of breast cancer and another 817 cases of prostate cancer. To perform a Mendelian randomization analysis on the phototype-cancer relationship, a genetic pigmentation score was required that met the following criteria: (1) the genetic pigmentation score was associated with phototype in controls; (2) the genetic pigmentation score was not associated with confounders in the relationship between phototype and cancer, and (3) the genetic pigmentation score was associated with cancer only through its association with phototype. Once this genetic score is available, the association between genetic pigmentation score and cancer can be identified as the association between phototype and cancer. RESULTS: The association between the genetic pigmentation score and phototype in controls showed that a higher genetic pigmentation score was associated with fair skin, blond hair, blue eyes and the presence of freckles. Applying the Mendelian randomization analysis, we verified that there was no association between the genetic pigmentation score and cancers of the breast and prostate. CONCLUSIONS: Phototype is not associated with breast or prostate cancer.

PGC-1α as a Biomarker of Physical Activity-Protective Effect on Colorectal Cancer.

Colorectal cancer is a significant public health concern. As a multistage and multifactorial disease, environmental and genetic factors interact at each stage of the process, and an individual's lifestyle also plays a relevant role. We set out to review the scientific evidence to study the need to investigate the role of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene as a biomarker of the physical activity's (PA) effect on colorectal cancer. PA is a protective factor against colorectal cancer and usually increases the expression of PGC-1α This gene has pleiotropic roles and is the main regulator of mitochondrial functions. The development of colorectal cancer has been associated with mitochondrial dysfunction; in addition, alterations in this organelle are associated with colorectal cancer risk factors, such as obesity, decreased muscle mass, and the aging process. These are affected by PA acting, among other aspects, on insulin sensitivity and oxygen reactive species/redox balance. Therefore, this gene demands special attention in the understanding of its operation in the consensual protective effect of PA in colorectal cancer. A significant amount of indirect evidence points to PGC-1α as a potential biomarker in the PA-protective effect on colorectal cancer. The article focuses on the possible involvement of PGC-1α in the protective role that physical activity has on colorectal cancer. This is an important topic both in relation to advances in prevention of the development of this widespread disease and in its therapeutic treatment. We hope to generate an initial hypothesis for future studies associated with physical activity-related mechanisms that may be involved in the development or prevention of colorectal cancer. PGC-1α is highlighted because it is the main regulator of mitochondrial functions. This organelle, on one hand, is positively stimulated by physical activity; on the other hand, its dysfunction or reduction increases the probability of developing colorectal cancer. Therefore, we consider the compilation of existing information about the possible ways to understand the mechanisms of this gene to be highly relevant. This study is based on evidence of PGC-1α and physical activity, on PGC-1α and colorectal cancer, on colorectal cancer and physical activity/inactivity, and the absence of studies that have sought to relate all of these variables. Cancer Prev Res; 11(9); 523-34. ©2018 AACR.

Reproductive risk factors in breast cancer and genetic hormonal pathways: a gene-environment interaction in the MCC-Spain project.

BACKGROUND: Reproductive factors are well known risk factors for breast cancer; however, little is known about how genetic variants in hormonal pathways interact with that relationship. METHODS: One thousand one hundred thirty nine cases of breast cancer in women and 1322 frequency-matched controls were compared. Genetic variants in hormonal pathways (identified in the Kyoto Encyclopedia of Genes and Genomes) were screened according to their relationship with breast cancer using the Cochran-Armitage statistic. Information on reproductive factors was obtained using a face-to-face questionnaire. The interaction among the selected genetic variants and reproductive factors was tested with logistic regression. RESULTS: Concerning C allele in rs2229712, compared to nulliparity in non-carriers the ORs for 1-2 and > 2 deliveries were 0.48 (0.28-0.81) and 0.34 (0.19-0.59), and in C carriers they were 0.92 (0.42-1.98) and 0.71 (0.31-1.61). Similar results were found in women carrying the C allele in rs1269851. Carriers of Allele T in rs35652107 and allele C in rs6018027 had the delivery number effect more pronounced. CONCLUSIONS: The number of deliveries had a dose-response protective effect on breast cancer; women carrying C allele in rs2229712 did not benefit from this protective effect.

Validating a breast cancer score in Spanish women. The MCC-Spain study.

A breast-risk score, published in 2016, was developed in white-American women using 92 genetic variants (GRS92), modifiable and non-modifiable risk factors. With the aim of validating the score in the Spanish population, 1,732 breast cancer cases and 1,910 controls were studied. The GRS92, modifiable and non-modifiable risk factor scores were estimated via logistic regression. SNPs without available genotyping were simulated as in the aforementioned 2016 study. The full model score was obtained by combining GRS92, modifiable and non-modifiable risk factor scores. Score performances were tested via the area under the ROC curve (AUROC), net reclassification index (NRI) and integrated discrimination improvement (IDI). Compared with non-modifiable and modifiable factor scores, GRS92 had higher discrimination power (AUROC: 0.6195, 0.5885 and 0.5214, respectively). Adding the non-modifiable factor score to GRS92 improved patient classification by 23.6% (NRI = 0.236), while the modifiable factor score only improved it by 7.2%. The full model AUROC reached 0.6244. A simulation study showed the ability of the full model for identifying women at high risk for breast cancer. In conclusion, a model combining genetic and risk factors can be used for stratifying women by their breast cancer risk, which can be applied to individualizing genetic counseling and screening recommendations.

The RS4939827 polymorphism in the SMAD7 GENE and its association with Mediterranean diet in colorectal carcinogenesis.

BACKGROUND: The objective of our investigation is to study the relationship between the rs4939827 SNP in the SMAD7 gene, Mediterranean diet pattern and the risk of colorectal cancer. METHODS: We examined 1087 cases of colorectal cancer and 2409 population controls with available DNA samples from the MCC-Spain study, 2008-2012. Descriptive statistical analyses, and multivariate logistic mixed models were performed. The potential synergistic effect of rs4939827 and the Mediterranean diet pattern was evaluated with logistic regression in different strata of of adherence to the Mediterranean diet and the genotype. RESULTS: High adherence to Mediterrenean diet was statistically significantly associated with colorectal cancer risk. A decreased risk for CRC cancer was observed for the CC compared to the TT genotype (OR = 0.65 and 95% CI = 0.51-0.81) of the rs4939827 SNP Also, we could show an association between the Mediterranean diet pattern (protective factor) and rs4939827. Although the decreased risk for the CC genotype was slightly more pronounced in subjects with high adherence to Mediterrenean diet, there was no statistically significant synergistic effect between genotype CC and adherence to the Mediterranean dietary pattern factors. CONCLUSION: The SMAD7 gene and specifically the allele C could be protective for colorectal cancer. An independent protective association was also observed between high adherence Mediterranean diet pattern and CRC risk. Findings form this study indicate that high adherence to Mediterranean diet pattern has a protective role for CRC cancer probably involving the Tumor Growth Factor- ß pathway in this cancer.

Alterations in PGC1α expression levels are involved in colorectal cancer risk: a qualitative systematic review.

BACKGROUND: Colorectal cancer (CRC) is a major global public health problem and the second leading cause of cancer-related death. Mitochondrial dysfunction has long been suspected to be involved in this type of tumorigenesis, as supported by an accumulating body of research evidence. However, little is known about how mitochondrial alterations contribute to tumorigenesis. Mitochondrial biogenesis is a fundamental cellular process required to maintain functional mitochondria and as an adaptive mechanism in response to changing energy requirements. Mitochondrial biogenesis is regulated by peroxisome proliferator-activated receptor gamma coactivator 1-α (PPARGC1A or PGC1α). In this paper, we report a systematic review to summarize current evidence on the role of PGC1α in the initiation and progression of CRC. The aim is to provide a basis for more comprehensive research. METHODS: The literature search, data extraction and quality assessment were performed according to the document Guidance on the Conduct of Narrative Synthesis in Systematic Reviews and the PRISMA declaration. RESULTS: The studies included in this review aimed to evaluate whether increased or decreased PGC1α expression affects the development of CRC. Each article proposes a possible molecular mechanism of action and we create two concept maps. CONCLUSION: Our systematic review indicates that altered expression of PGC1α modifies CRC risk. Most studies showed that overexpression of this gene increases CRC risk, while some studies indicated that lower than normal expression levels could increase CRC risk. Thus, various authors propose PGC1α as a good candidate molecular target for cancer therapy. Reducing expression of this gene could help to reduce risk or progression of CRC.