Stern, Mariana Carla

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

Abstract INTRODUCTION The Cancer Research Education and Engagement (CaRE2) Health Equity Center seeks to eliminate cancer disparities within Black and Latinx communities through research, training, education, and community engagement. The goal of this presentation is to share the unique model of community engagement that was implemented by the CaRE2 Center's Community Outreach Core (COC) during the COVID-19 pandemic. METHODS During the COVID-19 pandemic, the COC hosted community outreach events to address prostate and pancreatic cancer disparities. We overcame the challenges of COVID-19 by hosting these programs over Zoom, Facebook, and Twitter and allowing participants to interact and ask questions. The use of these platforms allowed us to develop and implement the innovative “bed to bedside” model, which allowed participants to gain a well-rounded understanding of the cancer process from cancer survivors, physicians, and researchers of color. The goal of these events were to 1) increase awareness of the importance of prostate and pancreatic cancer screening, 2) educate patients and community members about potential prostate and pancreatic cancer treatments, 3) raise awareness on prostate and pancreatic cancer research, and 4) address the causes and solutions to prostate and pancreatic cancer disparities in the Black and Latinx community. RESULT A total of 4 events were conducted between September and November of 2021, reaching a total of 30 persons directly and about 30 more through social media. At each event, evidence-based prostate cancer and pancreatic cancer education was disseminated. Of the attendees, 48% identified as Black or African American and 14% as Latino(x). Attendees were given the option to provide feedback and 90% of attendees agreed or strongly agreed that the presentations met their expectations. One benefit of conducting outreach activities via these platforms was the ability for more individuals to attend and the elimination of transportation barriers. Participants reported that attending virtually was easy to navigate and provided a suitable environment given the ongoing pandemic. Participants also reported that they enjoyed the “bed to bedside” model and shared that hearing from a survivor of color led to them feeling more comfortable in considering cancer screening. CONCLUSION The Care2 COC, in partnership with the community, is addressing disparities in the Black and Latinx population. One of the barriers that we had to overcome was continuing community outreach during the COVID-19 pandemic. The decision to provide health education outreach over social platforms, was essential to maintain our reach and impact. This allowed for the implementation of the “bed to bedside” model that included the different perspectives of care. We concluded that this model was effective and helped normalize the treatment process. We also concluded that outreach to the community should continue to provide cancer information via virtual formats especially as the COVID-19 related incidence and mortality begins to increase. Citation Format: Jessica Otero, Fern Webb, Folakemi Odedina, Nissa Askins, Linda Behar-Horenstein, Lourdes Baez-Conde, Mariana Stern, Sandra Suther, Renee Reams. Multifaceted approaches to engaging Black and Latinx populations: From bed to bedside [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-059.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Abstract Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P &lt; 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend &lt; 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.

Abstract B128 Background The B vitamin folate affects colorectal carcinogenesis through effects on nucleotide synthesis and possibly DNA methylation. Animal models and epidemiologic evidence suggest that folate from diet and supplements can prevent the development of colorectal cancer (CRC), but that high folate intake after adenomas or cancer are established may accelerate progression or recurrence. The chemotherapeutic agent 5-fluorouracil inhibits thymidylate synthase, a folate-metabolizing enzyme, and the effect of folate intake on treatment efficacy is unknown. Supplement use and folate intake are high among adults in the U.S., particularly with food supply fortification, and higher still among cancer patients and survivors. However, few studies have addressed use of folic acid-containing supplements (FAS) among colorectal cancer patients, how use changes after diagnosis, and what factors determine changes in FAS use. Methods The Colon Cancer Family Registry (CCFR) is a multicenter study of colorectal cancer cases, their family members and controls, recruited since 1998 at six sites in the United States, Australia and Canada. The current analysis includes 1,092 CRC cases with epidemiologic data available from questionnaires administered at enrollment, asking about supplement use and other risk factors before diagnosis, and from follow-up questionnaires about 5 years later. Baseline characteristics for cases who began using FAS (including multivitamins) after diagnosis were compared to those for cases who used FAS neither before nor after diagnosis. We used logistic regression models to evaluate associations between age, sex, CCFR site, race, education, income, lifetime exercise, smoking, body mass index, and diet and change in FAS use, adjusting each model for age, sex and site, when appropriate. Results FAS use before CRC diagnosis was 35.4%, while 55.1% of cases used FAS after diagnosis. Women were more likely to begin FAS use after diagnosis (OR 1.60, 95% CI 1.17-2.19). Current smokers were less likely than nonsmokers to begin FAS use (OR 0.63, 95% CI 0.40-0.97), as were those consuming more red meat (OR 0.38, 95% CI 0.21-0.70 for those in the highest versus lowest intake categories, ptrend=0.012). Subjects with higher fruit intake were more likely to begin FAS use (OR 1.95, 95% CI 1.16-3.30 for highest versus lowest intake, ptrend=0.013). We also observed a suggestive association between lifetime physical activity and change in FAS use for active versus less active subjects (OR 1.48, 95% CI 1.01-2.16), though there was no trend with increasing levels of physical activity (ptrend=0.27). Finally, we found that residents of non-U.S. countries were less likely to begin FAS use (OR 0.57, 95% CI 0.33-0.96 for Ontario, Canada and OR 0.21, 95% CI 0.11-0.38 for Australia). Conclusions: Our analysis showed substantial increases in the use of folic acid-containing supplements after diagnosis with colorectal cancer in CCFR participants, especially among women, U.S. residents, nonsmokers, and those who consumed more fruit and less meat. This study begins to characterize CRC patients likely to be using FAS, and suggests that its use is widespread. This finding is notable given evidence that folate may accelerate progression of colorectal cancer, and the unknown effect that FAS intake may have on the efficacy of cancer treatment and on survival. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B128.

AbstractBackground: Supplement use among cancer patients is high, and folic acid intake in particular may adversely affect the progression of colorectal cancer. Few studies have evaluated the use of folic acid–containing supplements (FAS) and its predictors in colorectal cancer patients.Objective: To assess the use of FAS, change in use, and its predictors after colorectal cancer diagnosis.Design: We used logistic regression models to investigate predictors of FAS use and its initiation after colorectal cancer diagnosis in 1,092 patients recruited through the Colon Cancer Family Registry.Results: The prevalence of FAS use was 35.4% before and 55.1% after colorectal cancer diagnosis (P = 0.004). Women were more likely than men to use FAS after diagnosis [odds ratio (OR), 1.47; 95% confidence interval (95% CI), 1.14-1.89], as were those consuming more fruit (Ptrend &lt; 0.0001) or vegetables (Ptrend = 0.001), and U.S. residents (P &lt; 0.0001). Less likely to use FAS after diagnosis were nonwhite patients (OR, 0.66; 95% CI, 0.45-0.97), current smokers (OR, 0.67; 95% CI, 0.46-0.96), and those with higher meat intake (Ptrend = 0.03). Predictors of FAS initiation after diagnosis were generally similar to those of FAS use after diagnosis, although associations with race and vegetable intake were weaker and those with exercise stronger.Conclusions: Our analysis showed substantial increases in the use of FAS after diagnosis with colorectal cancer, with use or initiation more likely among women, Caucasians, U.S. residents, and those with a health-promoting life-style.Impact: Studies of cancer prognosis that rely on prediagnostic exposure information may result in substantial misclassification. Cancer Epidemiol Biomarkers Prev; 19(8); 2023–34. ©2010 AACR.

Abstract A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)