Colorectal cancer risk factors in the detection of advanced adenoma and colorectal cancer

Several risk factors for colorectal cancer (CRC) have been identified. If individuals with risk factors are more likely to harbor cancer or it precursors screening programs should be targeted toward this population. We evaluated the predictive value of colorectal cancer risk factors for the detection of advanced colorectal adenoma in a population based CRC colonoscopy screening program. Data were collected in a multicenter trial conducted in the Netherlands, in which 6600 asymptomatic men and women between 50 and 75 years were randomly selected from a population registry. They were invited to undergo a screening colonoscopy. Based on a review of the literature CRC risk factors were selected. Information on risk factors was obtained from screening attendees through a questionnaire. For each CRC risk factor, we estimated its odds ratio (OR) relative to the presence of advanced neoplasia as detected at colonoscopy. Of the 1426 screening participants who underwent a colonoscopy, 1236 (86%) completed the risk questionnaire. 110 participants (8.9%) had advanced neoplasia. The following risk factors were significantly associated with advanced neoplasia detected by colonoscopy: age (OR: 1.06 per year; 95% CI: 1.03–1.10), calcium intake (OR: 0.99 per mg; 95% CI: 0.99–1.00), positive CRC family history (OR: 1.55 per first degree family member; 95%CI: 1.11–2.16) and smoking (OR: 1.75; 95%CI: 1.09–2.82). Elderly screening participants, participants with lower calcium intake, a CRC family history, and smokers are at increased risk of harboring detectable advanced colorectal neoplasia at screening colonoscopy.     

Colorectal cancer cases and relatives of cases indicate similar willingness to receive and disclose genetic information

Context: Recent developments in genetic testing allow us to detect individuals with inherited susceptibility to some cancers. Genetic testing to identify carriers of cancer-related mutations may help lower risk by encouraging preventive behaviors and surveillance. This study assessed willingness of colon cancer cases and relatives to receive genetic information that may indicate an increased risk for cancer, to whom they would disclose genetic information, and whether receiving genetic test results may influence future prevention behaviors among individuals enrolled in the Seattle Colorectal Cancer Family Registry. Methods: Incident invasive colorectal cancer cases were identified from the Puget Sound Surveillance Epidemiology and End Results (SEER) registry. In 2007, a sequential sample of cases and relatives (n = 147) were asked to respond to a questionnaire addressing study aims. The questionnaire was administered during a baseline or 5-year follow-up interview. Results: Patterns of response to each statement were similar between colorectal cancer cases and relatives. Both colorectal cases (95%) and relatives (95%) reported willingness to receive genetic information. Nearly all participants would tell their doctor the results of a genetic test (99% of cases; 98% of relatives), and all married participants would tell their spouses. Cases (96%) anticipated being slightly more likely than relatives (90%) to change their cancer screening behavior, but this difference was not statistically significant (p = 0.33). Conclusions: A high percentage of both colorectal cancer cases and relatives sampled from the Seattle Colorectal Cancer Family Registry are interested in identifying their genetic status, discussing their genetic status with their family and doctor, and adopting behavioral changes that may reduce cancer risk.     

Accuracy of cancer family histories: comparison of two breast cancer syndromes

Cancer risk programs rely on accurately reported family history information. This study compares the accuracy with which cancer sites and ages at diagnosis are reported by Li-Fraumeni syndrome (LFS) and hereditary breast-ovarian cancer syndrome (HBOCS) families undergoing genetic testing. We analyzed the accuracy of 191 cancer diagnoses among first-degree (FDRs) and second-degree (SDRs) relatives reported by 32 LFS and 52 HBOCS participants in genetic testing programs. Cancer diagnoses of relatives were more accurately reported in the HBOCS cohort (78%) than in the LFS cohort (52%). Almost all breast cancer diagnoses were accurately reported, whereas 74% of ovarian cancer diagnoses and only 55% of other LFS-related cancers were accurately reported. Age at diagnosis was accurate within 5 years for 60% of LFS relatives and 53% of HBOCS relatives. Factors correlating with accurate reporting of cancer history included: being member of BRCA1 family, higher education level, female historian, degree of closeness to affected relative, and having fewer than 5 affected FDRs and SDRs. Relying on verbal histories would not have altered eligibility for genetic testing among HBOCS historians, but fewer than half of LFS historians provided information that would have led to TP53 testing. Our data suggest that it may not be necessary to confirm breast cancer diagnoses routinely; however, documentation of other cancer types remains important for appropriate risk assessment and follow-up.     

The Joint Effects of Lifestyle Factors and Comorbidities on the Risk of Colorectal Cancer: A Large Chinese Retrospective Case-Control Study

Background

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. In previous epidemiologic studies, the respective correlation between lifestyle factors and comorbidity and CRC has been extensively studied. However, little is known about their joint effects on CRC.

Methods

We conducted a retrospective case-control study of 1,144 diagnosed CRC patients and 60,549 community controls. A structured questionnaire was administered to the participants about their socio-demographic factors, anthropometric measures, comorbidity history and lifestyle factors. Logistic regression model was used to calculate the odds ratio (ORs) and 95% confidence intervals (95%CIs) for each factor. According to the results from logistic regression model, we further developed healthy lifestyle index (HLI) and comorbidity history index (CHI) to investigate their independent and joint effects on CRC risk.

Results

Four lifestyle factors (including physical activities, sleep, red meat and vegetable consumption) and four types of comorbidity (including diabetes, hyperlipidemia, history of inflammatory bowel disease and polyps) were found to be independently associated with the risk of CRC in multivariant logistic regression model. Intriguingly, their combined pattern- HLI and CHI demonstrated significant correlation with CRC risk independently (OR_HLI: 3.91, 95%CI: 3.13–4.88; OR_CHI: 2.49, 95%CI: 2.11–2.93) and jointly (OR: 10.33, 95%CI: 6.59–16.18).

Conclusions

There are synergistic effects of lifestyle factors and comorbidity on the risk of colorectal cancer in the Chinese population.     

Healthy lifestyle,endoscopic screening,and colorectal cancer incidence and mortality in the United States: A nationwide cohort study

BackgroundHealthy lifestyle and screening represent 2 major approaches to colorectal cancer (CRC) prevention. It remains unknown whether the CRC-preventive benefit of healthy lifestyle differs by endoscopic screening status, and how the combination of healthy lifestyle with endoscopic screening can improve CRC prevention.Methods and findingsWe assessed lifestyle and endoscopic screening biennially among 75,873 women (Nurses’ Health Study, 1988 to 2014) and 42,875 men (Health Professionals Follow-up Study, 1988 to 2014). We defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption, and diet. We calculated hazard ratios (HRs) and population-attributable risks (PARs) for CRC incidence and mortality in relation to healthy lifestyle score according to endoscopic screening. Participants’ mean age (standard deviation) at baseline was 54 (8) years. During a median of 26 years (2,827,088 person-years) follow-up, we documented 2,836 incident CRC cases and 1,013 CRC deaths. We found a similar association between healthy lifestyle score and lower CRC incidence among individuals with and without endoscopic screening, with the multivariable HR per one-unit increment of 0.85 (95% CI, 0.80 to 0.90) and 0.85 (95% CI, 0.81 to 0.88), respectively (P-interaction = 0.99). The fraction of CRC cases that might be prevented (PAR) by endoscopic screening alone was 32% (95% CI, 31% to 33%) and increased to 61% (95% CI, 42% to 75%) when combined with healthy lifestyle (score = 5). The corresponding PAR (95% CI) increased from 15% (13% to 16%) to 51% (17% to 74%) for proximal colon cancer and from 47% (45% to 50%) to 75% (61% to 84%) for distal CRC. Results were similar for CRC mortality. A limitation of our study is that our study participants are all health professionals and predominantly whites, which may not be representative of the general population.ConclusionsOur study suggests that healthy lifestyle is associated with lower CRC incidence and mortality independent of endoscopic screening. An integration of healthy lifestyle with endoscopic screening may substantially enhance prevention for CRC, particularly for proximal colon cancer, compared to endoscopic screening alone.

Kai Wang and colleagues study contributions of healthy lifestyles and endoscopic screening to colorectal cancer outcomes.     

Association between family history of malignant neoplasm with colorectal adenomatous polyp in 40s aged relative person

PurposeWe assessed the association between a family history of malignancy and risk of colorectal adenoma among individuals aged 40–49 years.MethodsThe study population consisted of subjects, aged in their 40s, who underwent colonoscopy. Their family histories of cancer were collected with a self-administered questionnaire. A logistic regression model was used to assess the association between a family history of cancer and the risk of colorectal polyp.ResultsIn total, 2275 participants were included in the study. Univariate analysis showed that old age, male sex, current cigarette smoking, BMI > 25 kg/m², and a family history of colorectal cancer (CRC) were risk factors for the development of sporadic colorectal adenomatous polyps in these patients. A multivariate analysis showed that a family history of CRC or kidney cancer was associated with adenoma development. A family history of CRC was also a risk factor for advanced and multiple adenoma.ConclusionsThis study shows that a family history of CRC is a risk factor for advanced and multiple colorectal adenoma in people in their 40s. These results support earlier screening for colorectal neoplasms in individuals with a family history of CRC.     

High serum riboflavin is associated with the risk of sporadic colorectal cancer

BackgroundExperimental results indicate that riboflavin is involved in tumorigenesis. Data regarding the relationship between riboflavin and colorectal cancer (CRC) are limited, and findings vary between observational studies.DesignThis was a case–control retrospective study.ObjectiveThis study aimed to evaluate the associations between serum riboflavin level and sporadic CRC risk.MethodsIn total, 389 participants were enrolled in this study – including 83 CRC patients without family history and 306 healthy controls – between January 2020 and March 2021 at the Department of Colorectal Surgery and Endoscope Center at Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Age, sex, body mass index, history of polyps, disease conditions (e.g., diabetes), medications, and eight other vitamins were used as confounding factors. Adjusted smoothing spline plots, subgroup analysis, and multivariate logistic regression analysis were conducted to estimate the relative risk between serum riboflavin levels and sporadic CRC risk. After fully adjusting for the confounding factors, an increased risk of colorectal cancer was suggested for individuals with higher levels of serum riboflavin (OR = 1.08 (1.01, 1.15), p = 0.03) in a dose–response relationship.ConclusionsOur results support the hypothesis that higher levels of riboflavin may play a role in facilitating colorectal carcinogenesis. The finding of high levels of circulating riboflavin in patients with CRC warrants further investigation.     

Effectiveness of population-based colorectal cancer screening programme in down-staging

BackgroundThis is the first evaluation study to assess the demographic characteristics of the colorectal cancer (CRC) cases detected in the prevalent round of the population-based Colorectal Cancer Screening Programme (CRCSP) in Hong Kong and to explore the effectiveness of the programme on the stage distribution of CRC.MethodsThis study covered the period between 28 September 2016 and 31 December 2018. Information on CRC diagnosis, age and stage at diagnosis were retrieved and reviewed by the Hong Kong Cancer Registry (HKCaR). The CRC detection rate among CRCSP-screened participants and incidence rate among the Hong Kong general population were calculated respectively. The odds ratio (OR) was calculated to measure the strength of association and quantify the effect of CRCSP on stage shift between CRCSP-detected CRC cases and an age-matched cohort of CRC cases diagnosed outside the programme.ResultsThe CRC detection rate among participants of the CRCSP during the study period was 736.0/100,000, whereas the overall CRC incidence rate among general population of similar age groups was 393.7/100,000. For all ages and both sexes, the OR of stage I CRCSP-detected CRC compared to the CRC from the age-matched cohort was 3.91 (95%CI=3.41–4.48) and the OR dropped to 0.54 (95%CI=0.41–0.70) at stage IV. Meanwhile, the overall OR of CRCSP-detected CRC compared to CRC from the age-matched cohort dropped from 2.24 (95%CI=1.97–2.56) to 1.62 (95%CI=1.40–1.87) with increasing age.ConclusionThe present study has demonstrated the initial impact of the CRCSP on shifting the stage at diagnosis towards earlier stage. The benefit of stage-shift was similar for all ages from 60 to 77 in both sexes and seems to increase with younger age. Given the stage-dependent survival outcomes, this stage-shift could lead to a reduction in CRC-associated mortality in Hong Kong in future.     

Atrophic gastritis, Helicobacter pylori, and colorectal cancer risk: a case-control study

BACKGROUND: Helicobacter pylori is a major risk factor for atrophic gastritis and gastric cancer. Various extragastric manifestations of H. pylori infection have also recently been suggested. However, the correlation between H. pylori and colorectal cancer (CRC) is controversial. The aim of this study was to examine the correlation between H. pylori, serum gastrin level, and atrophic gastritis with CRC. MATERIALS AND METHODS: Subjects were patients with CRC; controls were participants of a health check-up program that was conducted between October 1998 and March 2002 at four hospitals in Nagano Prefecture. For 121 newly diagnosed CRC cases, two controls matched by age (within 3 years), gender, and residence were randomly selected from the program participants. We conducted questionnaires and obtained blood samples from the cases and their controls. Consequently, the CRC cancer pairs consisted of 113 cases and 226 controls. RESULTS: Neither H. pylori infection nor gastrin level nor atrophic gastritis showed any association with a risk for CRC. However, serologically determined atrophic gastritis demonstrated significant elevation in odds ratios (ORs) for rectal cancer (OR = 3.15, 95% confidence interval; 1.19-8.35). CONCLUSIONS: Gastric conditions such as chronic H. pylori infection and atrophic gastritis are unlikely to increase the risk for CRC, although atrophic gastritis may increase the risk of rectal cancer.     

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD?=?4.51, α?=?0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD?=?3.60, α?=?0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD?=?3.07, α?=?0.29; dominant HLOD?=?3.03, α?=?0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD?=?3.02, α?=?0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.     

Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Americans and is the second leading cause of cancer mortality. Only a minority ( approximately 5%) of familial CRC can be explained by known genetic variants. To identify susceptibility genes for familial colorectal neoplasia, the colon neoplasia sibling study conducted a comprehensive, genome-wide linkage scan of 194 kindreds. Clinical information (histopathology, size and number of polyps, and other primary cancers) was used in conjunction with age at onset and family history for classification of the families into five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancer) prior to analysis. By expanding the traditional affected-sib-pair design to include unaffected and discordant sib pairs, analytical power and robustness to type I error were increased. Sib-pair linkage statistics and Haseman-Elston regression identified 19 linkage peaks, with interesting results for chromosomes 1p31.1, 15q14-q22, 17p13.3, and 21. At marker D1S1665 (1p31.1), there was strong evidence for linkage in the multiple-cancer subgroup (p = 0.00007). For chromosome 15q14-q22, a linkage peak was identified in the full-sample (p = 0.018), oligopolyposis (p = 0.003), and young (p = 0.0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome (HMPS) in families of Ashkenazi descent. We provide compelling evidence linking this region in families of European descent with oligopolyposis and/or young age at onset (相似文献   

The impact on clinical outcome of high prevalence of diabetes mellitus in taiwanese patients with colorectal cancer

ABSTRACT: BACKGROUND: Both colorectal cancer (CRC) and diabetes mellitus (DM) are important public health problems worldwide. As there are controversies about survival impact on CRC patients with preexisting DM, the purpose of the present study is to evaluate the incidence and the survival impact of preexisting DM on the long-term outcomes of patients with CRC in Taiwan. METHODS: From January 2002 to December 2008, 1,197 consecutive patients with histologically proven primary CRC, who received surgical treatment at a single institution, were enrolled. The clinicopathologic features between these patients with and without DM were retrospectively investigated. Moreover, we intended to analyze the impact of DM on overall survival (OS) and cancer-specific survival (CSS) rates. RESULTS: Of 1,197 CRC patients, 23.6% of patients had either a reported history of DM or were currently taking one or more diabetes-controlling medications. CRC patients with DM were significantly older than those without DM (P <0.001), and had a higher incidence of cardiac disease and higher body mass index than those without DM (both P < 0.001). There were no significant differences in gender, tumor size, tumor location, histological type, AJCC/UICC cancer stage, vascular invasion, perineural invasion, comorbidity of pulmonary disease or renal disease, and OS, and CSS between two groups. Additionally, DM patients had a higher incidence of second malignancy than patients without DM (9.54% vs 6.01%, P = 0.040). CONCLUSIONS: A considerably high prevalence of DM in CRC patients but no significant impact of DM on survival was observed in the single-institution retrospective study, regardless of cancer stages and tumor locations. Therefore, treatment strategies for CRC patients with DM should be the same as patients without DM.     

Temporal and geographical variations in colorectal cancer incidence in Northern Iran 2004–2013

Introduction: Colorectal cancer (CRC) is one of the most common cancers in the Golestan province, Northern Iran. The purpose of this study is to describe colorectal cancer incidence patterns and trends in the province 2004–2013.Methods: Data on CRC cases were obtained from the Golestan Population-based Cancer Registry (GPCR). The GPCR is a high-quality cancer registry that collects data on primary cancers according to internationally accepted standard protocols. Age-standardized Incidence rates (ASR) were calculated and the 10-year trend quantified using the average annual percentage change (AAPC) from Joinpoint regressions.Results: The overall ASR of CRC were higher in men (14.8 per 100,000 person-years) and the urban populations (35.4), relative to women (11.5) and the rural populations (17.1), respectively. The overall incidence rate was observed to significantly increase 2004–2013 in men (AAPC = 7.3; 95%CI: 2.9–11.8) and women (AAPC = 6.6; 95%CI: 2.7–10.6). The analysis also showed that urban areas (AAPC = 8.1; 95%CI: 2.4–14.1) had a relatively more rapid increase in rates compared to rural areas (AAPC = 6.9; 95%CI: 2.2–11.7).Conclusions: CRC incidence rates in Golestan have been rising during the most recent decade, with a higher incidence and more rapid increases among men and the urban populations. The underlying risk factors should be assessed in the context of developing CRC prevention interventions in Golestan.     

FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer

Colorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.Subject terms: Cancer, Endocrine system and metabolic diseases     

Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families.

Germ-line BRCA1 and BRCA2 mutations account for most of familial breast-ovarian cancer. In Ashkenazi Jews, there is a high population frequency (approximately 2%) of three founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. This study examined the frequency of these mutations in a series of Ashkenazi women with ovarian cancer unselected for family history, compared with the frequency of these mutations in families ascertained on the basis of family history of at least two affected women. Penetrance was compared, both according to the method of family ascertainment (i.e., on the basis of an unselected ovarian cancer proband vs. on the basis of family history) and for the BRCA1 founder mutations compared with the BRCA2 6174delT mutation. There was a high frequency (10/22; [45%]) of germ-line mutations in Ashkenazi women with ovarian cancer, even in those with minimal or no family history (7/18 [39%]). In high-risk Ashkenazi families, a founder mutation was found in 59% (25/42). Families with any case of ovarian cancer were significantly more likely to segregate a founder mutation than were families with site-specific breast cancer. Penetrance was higher in families ascertained on the basis of family history than in families ascertained on the basis of an unselected proband, but this difference was not significant. Penetrance of BRCA1 185delAG and BRCA1 5382insC was significantly higher than penetrance of BRCA2 6174delT (hazard ratio 2.1 [95% CI 1.2-3.8]; two-tailed P = .01). Thus, the high rate of germ-line BRCA1/BRCA2 mutations in Ashkenazi women and families with ovarian cancer is coupled with penetrance that is lower than previously estimated. This has been shown specifically for the BRCA2 6174delT mutation, but, because of ascertainment bias, it also may be true for BRCA1 mutations.     

HER2-specific chimeric antigen receptor-T cells for targeted therapy of metastatic colorectal cancer

Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdc^em26cd52Il2rg^em26Cd22/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2⁺ CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.Subject terms: Cancer models, Colorectal cancer, Tumour biomarkers, Cancer therapy, Metastasis     

Differences in DNA methylation by extent of breast cancer family history in unaffected women

Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = ?46.8%, 0.1%), 17.9% (95%CI = ?39.5%, 3.7%) and 11.4% (95% CI = ?20.3%, ?2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = ?28.8%, ?7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors.     

Germline HOXB13 p.Gly84Glu mutation and risk of colorectal cancer

Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P = 0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR = 2.8; 95%CI: 1.2–6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation.