Clinical and Genetic Factors to Inform Reducing Colorectal Cancer Disparitites in African Americans

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer in the U.S. with 140,250 cases and 50,630 deaths for 2018. Prevention of CRC through screening is effective. Among categorized races in the U.S., African Americans (AAs) show the highest incidence and death rates per 100,000 when compared to Non-Hispanic Whites (NHWs), American Indian/Alaskan Natives, Hispanics, and Asian/Pacific Islanders, with an overall AA:NHW ratio of 1.13 for incidence and 1.32 for mortality (2010-2014, seer.cancer.gov). The disparity for CRC incidence and worsened mortality among AAs is likely multifactorial and includes environmental (e.g., diet and intestinal microbiome composition, prevalence of obesity, use of aspirin, alcohol, and tobacco use), societal (e.g., socioeconomic status, insurance and access to care, and screening uptake and behaviors), and genetic (e.g., somatic driver mutations, race-specific variants in genes, and inflammation and immunological factors). Some of these parameters have been investigated, and interventions that address specific parameters have proven to be effective in lowering the disparity. For instance, there is strong evidence raising screening utilization rates among AAs to that of NHWs reduces CRC incidence to that of NHWs. Reducing the age to commence CRC screening in AA patients may further address incidence disparity, due to the earlier age onset of CRC. Identified genetic and epigenetic changes such as reduced MLH1 hypermethylation frequency, presence of inflammation-associated microsatellite alterations, and unique driver gene mutations (FLCN and EPHA6) among AA CRCs will afford more precise approaches toward CRC care, including the use of 5-fluorouracil and anti-PD-1

ArterioVenous Malformation within Jejunal Diverticulum: An Unusual Cause of Massive Gastrointestinal Bleeding

Massive gastrointestinal (GI) bleeding can occur with multiple jejunal diverticulosis. However, significant bleeding in the setting of few diverticulae is very unusual and rare. We report a case of massive gastrointestinal bleeding from an arteriovenous malformation (AVM) within a jejunal diverticulum to underscore the significance of such coexisting pathologies. Mesenteric angiogram was chosen to help identify the source of bleeding and to offer an intervention. Despite endovascular coiling, emergent intestinal resection of the bleeding jejunal segment was warranted to ensure definitive treatment. However several reports have shown jejunal diverticulosis as a rare cause of massive GI bleeding. The coexistence of jejunal diverticulum and AVM is rare and massive bleeding from an acquired Dieulafoy-like AVM within a diverticulum has never previously been described. Awareness of Dieulafoy-like AVM within jejunoileal diverticulosis is useful in preventing delay in treatment

Delayed Gastric Emptying after Laparoscopic Anterior Highly Selective and Posterior Truncal Vagotomy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75042/1/j.1572-0241.1995.tb09325.x.pd

Secondary Prevention of Colorectal Cancer: Is There an Optimal Follow-up for Patients with Colorectal Cancer?

Secondary prevention of colorectal cancer, as opposed to primary prevention, indicates that a person has already had the disease and there are steps being taken to prevent cancer recurrence, usually as metachronous tumors. This generally involves annual surveillance with colonoscopy after surgical removal of the initial cancer if some aspect of the colon remains. However, some familial cases may involve other modalities, such as cyclooxygenase inhibitors, as an adjunct after the initial operation. Genetic testing in suspected familial cases may identify candidates for secondary prevention. The timing for secondary prevention is critical to prevent recurrent advanced disease, which is detrimental to patient survival. Recommendations are often empiric, but some cases are based on the biological behavior of the tumor. Close follow-up with a competent health care provider, such as a gastroenterologist, is necessary to help prevent recurrence

Detection of Multiple Human Papillomavirus Genotypes in Anal Carcinoma

Infection with human papillomavirus (HPV) is a major risk factor for development of anal squamous cell carcinoma. Despite over 100 genotypes of the virus, HPV 16 and 18 are considered pathogenic as they are seen in the majority of cervical and anal cancers. We have employed a custom microarray to examine DNA for several HPV genotypes. We aimed to determine the accuracy of our microarray in anal cancer DNA for HPV genotypes compared to the DNA sequencing gold standard

5,10-Methylenetetrahydrofolate Reductase 677 and 1298 Polymorphisms, Folate Intake, and Microsatellite Instability in Colon Cancer

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n = 503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5′ exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7–8.4) and in current smokers (OR, 4.0; 95% CI, 1.6–9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16–0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26–1.10). Among those with adequate folate intake (>400 μg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC + 1298 AC/CC, OR, 0.09; 95% CI, 0.01–0.59; 677 CT/TT + 1298 AA, OR, 0.13; 95% CI, 0.02–0.85) compared with the combined wild-type genotypes (677 CC + 1298 AA). This protective effect was not evident among those with low folate (<400 μg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status

Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers

AbstractBackground & Aims: Colorectal tumors manifesting high-frequency microsatellite instability (MSI-H) develop genetically as a consequence of mutations in genes harboring repetitive DNA sequences. The activin type 2 receptor (ACVR2), possessing 2 polyadenine coding sequences, was identified as a mutational target, but it is not clear if expression is abrogated. Here, we analyzed MSI-H colorectal cancers for ACVR2 mutation and expression to assess if biallelic inactivation occurs. Methods: All 54 MSI-H colon cancers and 20 random microsatellite stable (MSS) tumors from a population-based cohort of 503 patients were analyzed for mutations in 2 A8 tracts (exon 3 and 10) of ACVR2 and the A10 tract of transforming growth factor β receptor 2 (TGFBR2). Additionally, we sequenced exon 10 of ACVR2 in select cancers. ACVR2 expression was determined by immunohistochemistry using an antibody targeting an epitope beyond the predicted truncated protein. Results: Forty-five of 54 MSI-H cancers (83%) showed mutation (A8 to A7) in the polyadenine tract of exon 10 compared with no MSS tumors. Of tumors with mutant ACVR2, 62% lacked protein expression but all MSS and MSI-H tumors with wild-type ACVR2 expressed protein. We found no evidence of loss of heterozygosity at the ACVR2 locus in MSS tumors. Comparatively, 69% of MSI-H cancers had frameshift mutation in TGFBR2. Conclusions: ACVR2 mutations are highly frequent in MSI-H colon cancers and in most cases cause loss of ACVR2 expression, indicating biallelic inactivation of the gene. Loss of activin signaling through mutation of ACVR2, similar to observations with TGFBR2, may be important in the genesis of MSI-H colorectal cancer

The inflammatory response in transgastric surgery: gastric content leak leads to localized inflammatory response and higher adhesive disease

Risk of gastric spillage during transgastric surgery is a potential complication of NOTES procedures. The aim of this study was to determine risk outcomes from gastric spillage in a rat survival model by measuring local and systemic inflammatory markers, adhesive disease, and morbidity. We performed a minilaparotomy with needle aspiration of 2 ml of gastric contents mixed with 2 ml of sterile saline (study group, SG) or 4 ml of sterile saline (control group, CG) injected into the peritoneal cavity of 60 male rats. Inflammatory markers (TNFα, IL-6, and IL-10) were analyzed at 1, 3, 6, and 24 h postoperatively by obtaining plasma levels and peritoneal washings. At necropsy, the peritoneal cavity was examined grossly for adhesions. Adhesions were seen more frequently in the SG versus the CG (100% vs. 33.3%, p &lt; 0.014). There was a significant difference in the peritoneal TNFα levels in the SG compared with the CG, which peaked 1 h after surgery (p &lt; 0.02). Both peritoneal IL-6 and IL-10 levels were higher in the SG versus the CG, which peaked 3 h after surgery (p &lt; 0.005 and p &lt; 0.001, respectively). All peritoneal inflammatory markers returned to undetectable levels at 24 h for both groups. Plasma cytokines were undetectable at all time intervals. The inflammatory response was found to be a localized and not systemic event, with plasma cytokine levels remaining normal while peritoneal washings revealed a brisk, short-lived localized inflammatory response. There was a significantly higher rate of adhesive disease in the SG compared with the CG; this, however did not translate into a difference in apparent clinical outcome. We conclude that gastric leakage in this NOTES rodent model induces a localized inflammatory response, followed by mild to moderate adhesive disease. This may be important in human NOTES

Activin Signaling in Microsatellite Stable Colon Cancers Is Disrupted by a Combination of Genetic and Epigenetic Mechanisms

Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers.Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p<0.001) and ACVR2 promoter hypermethylation (p<0.05). ACVR2 LOH, but not promoter hypermethylation, correlated with CIN status. In colon cancer cell lines with fully methylated ACVR2 promoter, loss of ACVR2 mRNA and protein expression was restored with 5-Aza treatment. Loss of ACVR2 was associated with an increase in primary colon cancer volume (p<0.05).Only a small percentage of MSS colon cancers lose expression of activin signaling members. ACVR2 loss occurs through LOH and ACVR2 promoter hypermethylation, revealing distinct mechanisms for ACVR2 inactivation in both MSI and MSS subtypes of colon cancer

Charting the future of cancer health disparities research: A position statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138314/1/caac21404_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138314/2/caac21404.pd