Frequent epigenetic silencing of PCDH10 by methylation in human colorectal cancer

Purpose

Aberrant DNA methylation is common in cancer cells. Epigenetic alterations resulting in the loss of tumor suppression gene functions are frequently involved in tumor development and progression. Recently, methylation of PCDH10 was reported to be associated with multiple hematologic malignancies as well as some solid tumors. Whether the down-regulation of PCDH10 happens in CRC remains unknown.

Methods

Methylation status of PCDH10 was evaluated by methylation-specific PCR analysis. The effects of PCDH10 re-expression were determined in growth, colony formation, cell cycle, and invasion assays.

Results

In this study, we found that 100 % (8 of 8) of colorectal cancer cell lines were silenced for PCDH10, but not normal colorectal epithelial cells. Demethylation treatment confirmed that the reduced expression is associated closely with promoter methylation. Hyper-methylation of PCDH10 was also detected in 85 % of primary colorectal tumors, but not in adjacent normal colorectal tissues.

Conclusions

Our results suggest that PCDH10 is an important tumor suppression gene with key roles of suppressing cell proliferation, clonogenicity, and inhibiting cell invasion in the development of colorectal cancer. Thus, PCDH10 methylation may constitute a useful biomarker of colorectal cancer patients.     

Randomized, Controlled Trial of a Multimodal Intervention to Improve Cancer Screening Rates in a Safety-Net Primary Care Practice

Background

Cancer screening rates are suboptimal for low-income patients.

Objective

To assess an intervention to increase cancer screening among patients in a safety-net primary care practice.

Design

Patients at an inner-city family practice who were overdue for cancer screening were randomized to intervention or usual care. Screening rates at 1 year were compared using the chi-square test, and multivariable analysis was performed to adjust for patient factors.

Subjects

All average-risk patients at an inner-city family practice overdue for mammography or colorectal cancer (CRC) screening. Patients’ ages were 40 to 74 years (mean 53.9, SD 8.7) including 40.8 % African Americans, 4.2 % Latinos, 23.2 % with Medicaid and 10.9 % without any form of insurance.

Intervention

The 6-month intervention to promote cancer screening included letters, automated phone calls, prompts and a mailed Fecal Immunochemical Testing (FIT) Kit.

Main Measures

Rates of cancer screening at 1 year.

Key Results

Three hundred sixty-six patients overdue for screening were randomly assigned to intervention (n?=?185) or usual care (n?=?181). Primary analysis revealed significantly higher rates of cancer screening in intervention subjects: 29.7 % vs. 16.7 % for mammography (p?=?0.034) and 37.7 % vs. 16.7 % for CRC screening (p?=?0.0002). In the intervention group, 20 % of mammography screenings and 9.3 % of CRC screenings occurred at the early assessment, while the remainder occurred after repeated interventions. Within the CRC intervention group 44 % of screened patients used the mailed FIT kit. On multivariable analysis the CRC screening rates remained significantly higher in the intervention group, while the breast cancer screening rates were not statistically different.

Conclusions

A multimodal intervention significantly increased CRC screening rates among patients in a safety-net primary care practice. These results suggest that relatively inexpensive letters and automated calls can be combined for a larger effect. Results also suggest that mailed screening kits may be a promising way to increase average-risk CRC screening.     

p42.3: A promising biomarker for the progression and prognosis of human colorectal cancer

Purpose

As a novel cell cycle-related gene, p42.3 has been shown to play a key role in the cell proliferation and tumorigenicity of gastric cancer. To date, the association between p42.3 and colorectal cancer (CRC) has not been reported. This study investigated the expression of p42.3 and its potential role in human colorectal cancers.

Methods

Real-time polymerase chain reaction and western blotting were used to evaluate p42.3 mRNA and protein expression in 14 pairs of fresh frozen CRC samples, matched with adjacent normal mucosa. The p42.3 protein was evaluated by immunohistochemistry using CRC tissue microarrays, which included 212 CRC specimens and corresponding normal colorectal mucosa. The expression profiles of p42.3 in CRC tissues were analyzed against clinicopathological factors and post-surgical survival status. The expression profiles of p42.3 were also investigated in six human colon carcinoma cell lines.

Results

p42.3 was demonstrated to be over-expressed in colorectal cancer tissues compared with normal mucosa in the 14 tissue pairs (P = 0.011) and was significantly higher in patients with poor tumor differentiation (P = 0.045); patients positive for p42.3 expression had a poorer prognosis than those not expressing this protein (P = 0.033). In a multivariate survival analysis, p42.3 expression was identified as an independent prognostic factor for CRC patients (P = 0.030).

Conclusions

The results indicated that p42.3 might play an important role in the progression of CRC, and it has a great value for assessing CRC patient prognosis after surgery.     

Quantitative profiling of CpG island methylation in human stool for colorectal cancer detection

Purpose

The aims of this study were to investigate the use of quantitative CGI methylation data from stool DNA to classify colon cancer patients and to relate stool CGI methylation levels to those found in corresponding tissue samples.

Methods

We applied a quantitative methylation-specific PCR assay to determine CGI methylation levels of six genes, previously shown to be aberrantly methylated during colorectal carcinogenesis. Assays were performed on DNA from biopsies of “normal” mucosa and stool samples from 57 patients classified as disease-free, adenoma, or cancer by endoscopy, and in tumour tissue from cancer patients. Additionally, CGI methylation was analysed in stool DNA from an asymptomatic population of individuals covering a broad age range (mean?=?47?±?24 years)

Results

CGI methylation levels in stool DNA were significantly higher than in DNA from macroscopically normal mucosa, and a significant correlation between stool and mucosa was observed for ESR1 only. Multivariate statistical analyses using the methylation levels of each CGI in stool DNA as a continuous variable revealed a highly significant (p?=?0.003) classification of cancer vs. non-cancer (adenoma + disease-free) patients (sensitivity?=?65 %, specificity?=?81 %).

Conclusion

CGI methylation profiling of stool DNA successfully identified patients with cancer despite the methylation status of CGIs in stool DNA not generally reflecting those in DNA from the colonic mucosa.     

Prevalence of Colorectal Neoplasia Among Young African Americans and Hispanic Americans

Background

The disproportionately higher incidence of and mortality from colorectal cancer (CRC) among African Americans (AA) led the American College of Gastroenterology to recommend screening starting at age 45 in 2005.

Aim

The purpose of this study was to determine the prevalence of colorectal neoplasia among 40–49-year-old inner city AA and Hispanic Americans (HA).

Methods

We reviewed the medical records of 2,435 inner city AA and HA who underwent colonoscopy regardless of indication and compared the prevalence of colorectal neoplasia between AA and HA patients. We used logistic regression models to calculate odds ratios (OR) and 95 % confidence intervals (CI).

Results

There were 2,163 AAs and 272 HA. There were 57 % women in both groups. A total of 158 (7 %) AA and 9 (3 %) HA (P = 0.014) underwent the procedures for CRC screening. When compared to HAs, AAs had higher prevalence of any polyp (35 vs. 18 %, OR = 2.53; 95 % CI 1.82–3.52). Overall, AA had higher prevalence of colorectal neoplasia (adenoma and cancer) when compared to HAs (16 vs. 10 %; OR = 1.68; 95 % CI 1.10–2.56).

Conclusion

We observed a higher frequency of colorectal neoplasia among 40–49-year-old AAs as compared to HAs suggesting an increased susceptibility to CRC risk in this population.     

TFAP2E hypermethylation was associated with survival advantage in patients with colorectal cancer

Purpose

Hypermethylation of TFAP2E (AP-2E) is associated with the chemotherapy-resistant in patients with colorectal cancer (CRC), but its implications on prognosis directly remain unknown. This study was aimed to investigate the role of AP-2E methylation status and other clinicopathologic parameters as predictors of prognosis.

Methods

We detected the methylation status of AP-2E in tumor and adjacent non-tumor tissues from 311 sporadic CRC patients by methylation-sensitive high-resolution melting analysis. Log-rank tests and multivariate Cox analyses were performed to evaluate the role of AP-2E methylation status and other clinicopathologic parameters as predictors of prognosis.

Results

Hypermethylation of AP-2E was detected in 61 % (190/311) tumor tissues. It occurred more frequently in tumors in earlier stages (I/II; P = 0.02), lower levels of tumor invasion (T1–T3; P = 0.04), fewer lymph nodes involved (N0; P < 0.01), and higher histologic grades (G1/G2; P < 0.01). The overall 5-year survival rates in hypermethylation and hypomethylation group were 76.91 and 47.17 % (P < 0.0001), respectively. AP-2E hypermethylation was significantly associated with a favorable clinical outcome with a hazard ratio of 0.486 (95 % CI 0.342–0.692, P < 0.0001) after controlling for age, gender, tumor location, histologic type, TNM staging, and histologic grade.

Conclusions

AP-2E was frequently hypermethylated in tumors from patients with CRC. Aberrant hypermethylation of AP-2E occurred more frequently in tumors with earlier stages, lower levels of tumor invasion, fewer lymph nodes involved, and higher histologic grades. AP-2E hypermethylation might be an independent predictor of survival advantage in patients with CRC.     

Stool Methylated DNA Markers Decrease Following Colorectal Cancer Resection—Implications for Surveillance

Background

Molecular changes associated with colorectal cancer (CRC) are detected by stool deoxyribonucleic acid testing but could persist following tumor resection.

Aims

We sought to determine whether methylated gene markers in stool normalize after CRC resection.

Methods

We studied stools from 22 CRC cases before and after subtotal resection and from 80 colonoscopy-normal controls. In blinded fashion, target genes (methylated NDRG4 and BMP3) were captured from stool supernatant, bisulfite-treated, and assayed by quantitative allele-specific real-time target and signal amplification. Results were dichotomized at 95 % specificity cutoffs.

Results

Among CRC cases, median methylated NDRG4 and BMP3 levels decreased dramatically (4- to 15-fold) following resection, p = 0.003 and p < 0.0001, respectively. Among the 14 cases with elevated preoperative levels, 13 (93 %) fell into the normal range after surgery, p = 0.0002. A case whose stool methylated NDRG4 level increased sharply after surgery was found to have recurrent CRC.

Conclusions

Methylated gene marker levels clear from stool following CRC resection unless disease is present. Postoperative stool marker levels are informative and may be of value in surveillance.     

Overexpression of CK20, MAP3K8 and EIF5A correlates with poor prognosis in early-onset colorectal cancer patients

Purpose

Due to ethnic, genetic and environmental factors, the clinical and molecular characteristics of Turkish colorectal cancer (CRC) patients are different from those of Western populations. The aim of this study was to clarify the relevant alterations of gene expression associated with colorectal carcinogenesis in early-onset patients and to identify specific biomarkers that could provide novel therapeutic molecular targets in this population.

Methods

The expression profiles of 114 different genes were evaluated using mRNA PCR arrays in 39 tumors and 20 surgical margin tissue samples from 39 sporadic CRC patients diagnosed at less than 50 years of age.

Results

The expression levels of IMPDH2, CK20, MAP3K8 and EIF5A were strongly up-regulated in CRC tissues compared with normal colorectal tissues (p < 0.05). The highly significant expression ratios of CK20, MAP3K8 and EIF5A observed in the colorectal tumors of patients predicted recurrence (p < 0.05). The expression of IMPDH2, CK20, MAP3K8 and EIF5A was significantly higher in the tumors of patients with short median survival (log-rank p value < 0.05). Progression-free survival was also significantly increased in patients with low expression of the EIF5A gene compared with those who exhibited high expression of this gene (log-rank p value < 0.05).

Conclusion

We demonstrated that high CK20, MAP3K8 and EIF5A expression levels were significant prognostic factors for poor overall survival in CRC patients. Further studies and validations are required; these genes may provide novel therapeutic molecular targets for CRC treatment, as well as new directions for the development of anticancer drugs.     

Incidence of Bacteremia Following Bronchoscopy with Argon Plasma Coagulation: A Prospective Study

Background

This evaluation was undertaken to determine the incidence of bacteremia and infectious complications associated with argon plasma coagulation (APC) procedures.

Methods

Consecutive patients undergoing bronchoscopy with APC for treatment of endobronchial lesions were studied. Venesection was performed for blood cultures within 60 s of the APC procedure. APC catheter washings were cultured. Patients with positive blood cultures were reviewed immediately. All patients underwent clinical review 1 and 12 weeks after APC.

Results

Forty-two patients underwent 44 APC procedures. Their mean age was 66 ± 12 years. One case (2.3 %) had bacteremia with Acinetobacter lwolfii. APC catheter washing culture was positive in 14 (31.8 %) procedures. No patient had clinical features suggesting infection and there were no complications. Phone review after 1 week revealed no complications. After 3 months, 8 (18 %) had died, all related to advanced lung malignancy and not to the APC procedure.

Conclusions

APC does not appear to increase the risk of bacteremia compared to airway insertion of the bronchoscope. Although contamination of the APC catheter with oropharyngeal commensal bacteria is common, clinically significant infection following the APC procedure is rare.     

Results from an American Society of Colon and Rectal Surgeons survey on the management of young-onset colorectal cancer

Background

Young patients with colorectal cancer (CRC) present a diagnostic and clinical challenge. The aim of our study was to survey the approaches to preoperative evaluation and clinical management of young patients with CRC by colorectal surgeons in North America.

Methods

A standard electronic survey was sent to the members of the American Society of Colon and Rectal Surgeons. The survey polled management decisions in various clinical scenarios for CRC patients less than 50 years old. Survey responses were collated and analyzed.

Results

One hundred ninety surgeons responded and 140 completed the entire survey (response rate 10 %). Eighty percent of surgeons would offer preoperative genetic testing if the patient’s family met the Amsterdam criteria compared to only 67 % if the criteria were not met. Of those offering preoperative tumor testing, 48 % test microsatellite instability, 19 % mismatch repair protein expression by immunohistochemistry, and 24 % offer both. Decisions regarding the extent of the resection for cancer were dependent on family history: Most members (86 %) would perform a segmental colectomy for CRC in a patient without family history. Eighty-four percent of respondents would offer a total abdominal colectomy if preoperative tests indicated Lynch syndrome. When questioned about MYH-associated polyposis, only 27 % recognized the appropriate diagnosis.

Conclusions

Among the American Society of Colon and Rectal Surgeons, family history influences preoperative testing and surgical management decisions. A significant portion of surgeons do not offer preoperative genetic testing, despite implications on operative management, postoperative surveillance, and screening of family members.     

Management of colorectal cancer in patients with inflammatory bowel disease

Background

This study evaluated the clinicopathological features and survival rates of patients with inflammatory bowel disease who developed colorectal cancer (CRC).

Methods

A retrospective review was performed on a prospectively maintained institutional database (1981–2011) to identify patients with inflammatory bowel disease who developed CRC. Clinicopathological parameters, management and outcomes were analysed.

Results

A total of 2,843 patients with inflammatory bowel disease were identified. One thousand six hundred and forty-two had ulcerative colitis (UC) and 1,201 had Crohn’s disease (CD). Following exclusion criteria, there were 29 patients with biopsy-proven colorectal carcinoma, 22 of whom had UC and 7 had CD. Twenty-six patients had a preoperative diagnosis of malignancy/dysplasia; 16 of these were diagnosed at surveillance endoscopy. Nodal/distant metastasis was identified at presentation in 47 and 71 % of the UC and CD group, respectively. Operative morbidity for UC and CD was 33 and 17 %, respectively. Despite the less favourable operative outcomes following surgery management of UC-related CRC, overall 5-year survival was significantly better in the UC group compared to the CD group (41 vs. 29 %; p = 0.04) reflecting the difference in stage at presentation between the two groups.

Conclusions

Patients who undergo surgery for UC-related CRC have less favourable short-term outcomes but present at a less advanced stage and have a more favourable long-term prognosis than similar patients with CRC and CD.     

Incidence and Survival of Colorectal Cancer Among Hispanics in the United States: A Population-Based Study

Background

Hispanics are the largest and fastest growing ethnic group in the United States (US).

Aims

We evaluated the incidence and survival of colorectal cancer (CRC) among this population.

Methods

Data from the surveillance, epidemiology, and end results program were used to calculate CRC age-adjusted and age-specific incidence rates in Hispanics during 1993–2007. Temporal trends in CRC incidence were examined using annual percent change (APC) and Poisson regression. The 1- and 5-year survival rates were calculated.

Results

The annual age-adjusted incidence rates for CRC in Hispanics of all ages declined from 47.4 per 100,000 in 1993–1997 to 43.8 per 100,000 in 2003–2007, with an APC during 1993–2007 equal to ?0.8/year. However, there was a 45 % increase in CRC incidence among Hispanic men and women aged 20–49 years that affected both the right and left colon. The proportions of CRC cases with regional (+37 %) and distant (+18 %) spread increased, now constituting 72 % of cases diagnosed at that age. The Poisson model confirmed the increasing CRC incidence in Hispanics aged 20–49 years during 1993–2007 while adjusting for sex and geographic region. The 1-year survival improved in younger Hispanics from approximately 86 % in 1993–1997 to 91 % in 2003–2007 with no significant improvement in 5-year survival. In Hispanics aged >50 years, no significant improvements in survival were observed.

Conclusions

The incidence of CRC in young Hispanic men and women has increased in the US. Most are diagnosed with regional or distant disease. No significant improvement in long-term survival was observed in young Hispanics with CRC.     

Changing Epidemiology of Colorectal Cancer Makes Screening Sigmoidoscopy Less Useful for Identifying Carriers of Colorectal Neoplasms

Background

There is renewed interest in flexible sigmoidoscopy (FS) colorectal cancer (CRC) screening following trials showing significantly reduced CRC incidence and mortality.

Aims

To evaluate the potential usefulness of FS screening in our population.

Methods

We examined rectosigmoid (RS) cancer epidemiology in our Jewish population using Israel National Cancer Registry data, computed by CRC site, age groups, and gender. We also reviewed endoscopy-screening publications for prevalence of RS and proximal advanced adenomas (AAP) and having both or either.

Results

During 1980–2008, there were 64,559 CRCs registered; 31.6 % were RS cancer which has now decreased to 29 % of men’s and 26 % of women’s CRC (both P < 0.01). In <50 year olds, RS cancer occurred in 42 % of males’ and 35 % of females’ CRC, and in the last 2 decades this ratio is unchanged. In 50–74 year olds, RS cancer decreased to stable levels of 32 % of males’ and 29 % females’ CRC (both P < 0.01). In ≥75 year olds, RS cancer progressively decreased to 24 % of males’ and 22 % females’ CRC (both P < 0.001). From endoscopy screening reports in 40–79 year olds, RS AAPs occurred in 2.0–5.8 %, being least in women, most in men, and not increased with aging. Some 50–57 % of screenees had both RS and proximal AAPs, least when aged 40–49 years at 25 %, women were 35 %, and with aging 40 %, but most in men at 70 %.

Conclusions

With the changing CRC epidemiology, having fewer RS neoplasms but more proximal cancer, the effectiveness of FS screening for identifying significant neoplasms decreases with screenees’ age and especially in females. These make FS screening less suitable for our aging and increasingly female population.     

RASSF1A, APC, ESR1, ABCB1 and HOXC9, but not p16INK4A, DAPK1, PTEN and MT1G genes were frequently methylated in the stage I non-small cell lung cancer in China

Purpose

To identify the DNA methylation biomarkers for the detection of the stage I non-small cell lung cancer (NSCLC).

Materials and methods

The methylated state of p16INK4A, ESR1, HOX9, RASSF1A, DAPK1, PTEN, ABCB1, MGMT, APC and MT1G genes that have been reported frequently methylated in lung cancer was determined using methylation-specific PCR in four lung cancer cell lines, 124 cancer tissues of the stage I NSCLC and 26 non-cancerous disease tissues.

Result

The RASSF1A (53/124, 42.74%), APC (49/123, 39.52%), ESR1 (37/124, 29.84%), ABCB1 (31/124, 24.19%, MT1G (25/124, 20.16%) and HOXC9 (17/124, 13.71%) genes were more frequently methylated in the lung tissue from the stage I NSCLC than the non-cancerous lesion patients (2/26, 7.69%, P < 0.01; 2/26, 7.69%, P < 0.01; 2/26, 7.69%, P < 0.05; 1/26, 3.85% P < 0.01; 0/26 0%, P value: <0.01; 0/26, 0%, P < 0.05, respectively). p16INK4A was methylated in 28/124 (22.56%) of cancer tissues and 2/26 (7.69%) of non-cancerous tissues (P value >0.05). No significant association between the methylated state of the genes and the smoking, age or the pathologic types (squamous carcinoma, adenoma and the mixed types) was found. However, p16INK4A methylation was more frequently detected in the male (23/80, 28.75%) than the female (5/44, 11.36%, P > 0.05) patients. MGMT was barely methylated: 1/67, 1.49%), while DAPK1 and PTEN were not at all methylated in the cancer groups.

Conclusions

Methylation analysis in tissue of RASSF1A, APC, ESR1, ABCB1 and HOXC9 genes confirmed 79.8% of the existing diagnosis for the stage I NSCLC at specificity: 73.1%. The insufficiency of predicting disease onset in China, using the previously recommended targets (MGMT, DAPK1 and PTEN) in the United States reflects a potential disease disparity between these two populations. Alternatively, methylated state of this set of genes may be more specific to the late rather than the early stage of NSCLC.     

Low-grade dietary-related inflammation and survival after colorectal cancer surgery

Purpose

Prolong inflammation is a central process observed in several chronic conditions and may be responsible for survival. There is an increasing evidence showing the role of diet in inflammation and habitual diet may be responsible for low-grade inflammation. The purpose of our study was to assess the effect of inflammatory properties of habitual diet measured by the Dietary Inflammatory Index (DII) on survival among surgical patients treated for colorectal cancer (CRC).

Methods

A follow-up study among 689 CRC patients (mean age 58 years, ±8.9; 56.7 % males) treated surgically was performed in Krakow, Poland. Habitual diet was assessed by a standardized semiquantitative food frequency questionnaire. Next, 23 dietary items were used to calculate DIIs. Vital records were verified to determine status of the participants.

Results

Study has shown linear association between DII and survival time among CRC patients with totally removed cancer treated by chemotherapy (b = ?0.13, p = 0.024). After adjustment for several important covariates, DII was associated with survival during up to 3 years after surgery, but only in patients without distant metastases (3-year HR_DII>?2.27 = 0.61, 95 % CI 0.38–0.99).

Conclusions

The results of the investigation have shown the usefulness of the DII as a potential predictor of survival among patients without distant metastases treated surgically for CRC.     

Quality colonoscopy and risk of interval cancer in Lynch syndrome

Purpose

Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological features of these cancers, and (3) quality of the previous colonoscopy.

Methods

Approximately 2,200 medical reports from proven and obligate mutation carriers identified at the Dutch Lynch Syndrome Registry and two large hospitals were retrospectively analyzed for the presence of an interval cancer defined as CRC diagnosed within 24 months of previous colonoscopy.

Results

Thirty-one interval cancers were detected in 29 patients (median age of 52 [range 35–73]), after a median time of 17 months. All were MLH1 or MSH2 mutation carriers, and 39 % had a previous CRC. In patients without previous surgery for CRC, 84 % was proximally located. Of all interval cancers, 77 % were at local stage (T1–3N0Mx). In three patients (9 %) with an incomplete previous colonoscopy, CRC was located in the unexamined colon. In six of the nine patients with an adenoma during previous colonoscopy, the cancer was detected in the same colonic segment as the previously removed adenoma.

Conclusions

Interval cancers were detected in MLH1 and MSH2 mutation carriers, especially in those with a history of previous CRC and between 40 and 60 years. Interval cancer could be related to incompleteness of previous endoscopy and possibly residual adenomatous tissue. Further reduction of the interval cancer risk may be achieved by optimizing endoscopy quality and individualization of surveillance guidelines.     

Get Screened: A Randomized Trial of the Incremental Benefits of Reminders, Recall, and Outreach on Cancer Screening

BACKGROUND

Rates of breast cancer (BC) and colorectal cancer (CRC) screening are particularly low among poor and minority patients. Multifaceted interventions have been shown to improve cancer-screening rates, yet the relative impact of the specific components of these interventions has not been assessed. Identifying the specific components necessary to improve cancer-screening rates is critical to tailor interventions in resource limited environments.

OBJECTIVE

To assess the relative impact of various components of the reminder, recall, and outreach (RRO) model on BC and CRC screening rates within a safety net practice.

DESIGN

Pragmatic randomized trial.

PARTICIPANTS

Men and women aged 50–74 years past due for CRC screen and women aged 40–74 years past due for BC screening.

INTERVENTIONS

We randomized 1,008 patients to one of four groups: (1) reminder letter; (2) letter and automated telephone message (Letter + Autodial); (3) letter, automated telephone message, and point of service prompt (Letter + Autodial + Prompt); or (4) letter and personal telephone call (Letter + Personal Call).

MAIN MEASURES

Documentation of mammography or colorectal cancer screening at 52 weeks following randomization.

KEY RESULTS

Compared to a reminder letter alone, Letter + Personal Call was more effective at improving screening rates for BC (17.8 % vs. 27.5 %; AOR 2.2, 95 % CI 1.2–4.0) and CRC screening (12.2 % vs. 21.5 %; AOR 2.0, 95 % CI 1.1–3.9). Compared to letter alone, a Letter + Autodial + Prompt was also more effective at improving rates of BC screening (17.8 % vs. 28.2 %; AOR 2.1, 95 % CI 1.1–3.7) and CRC screening (12.2 % vs. 19.6 %; AOR 1.9, 95 % CI 1.0–3.7). Letter + Autodial was not more effective than a letter alone at improving screening rates.

CONCLUSIONS

The addition of a personal telephone call or a patient-specific provider prompt were both more effective at improving mammogram and CRC screening rates compared to a reminder letter alone. The use of automated telephone calls, however, did not provide any incremental benefit to a reminder letter alone.     

DNA Methylation of MicroRNA-124a Is a Potential Risk Marker of Colitis-Associated Cancer in Patients with Ulcerative Colitis

Background

Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation.

Aim

We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients.

Methods

Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry.

Results

Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3 %, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2 %, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors.

Conclusions

MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC.