Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Increasing Rates of Surgery for Patients With Nonmalignant Colorectal Polyps in the United States.

BACKGROUND & AIMS: Despite the availability of endoscopic therapy, many patients in the United States undergo surgical resection for nonmalignant colorectal polyps. We aimed to quantify and examine trends in the use of surgery for nonmalignant colorectal polyps in a nationally representative sample. METHODS: We analyzed data from the Healthcare Cost and Utilization Project National Inpatient Sample for 2000 through 2014. We included all adult patients who underwent elective colectomy or proctectomy and had a diagnosis of either nonmalignant colorectal polyp or colorectal cancer. We compared trends in surgery for nonmalignant colorectal polyps with surgery for colorectal cancer and calculated age, sex, race, region, and teaching status/bed-size-specific incidence rates of surgery for nonmalignant colorectal polyps. RESULTS: From 2000 through 2014, there were 1,230,458 surgeries for nonmalignant colorectal polyps and colorectal cancer in the United States. Among those surgeries, 25% were performed for nonmalignant colorectal polyps. The incidence of surgery for nonmalignant colorectal polyps has increased significantly, from 5.9 in 2000 to 9.4 in 2014 per 100,000 adults (incidence rate difference, 3.56; 95% confidence interval 3.40-3.72), while the incidence of surgery for colorectal cancer has significantly decreased, from 31.5 to 24.7 surgeries per 100,000 adults (incidence rate difference, -6.80; 95% confidence interval -7.11 to -6.49). The incidence of surgery for nonmalignant colorectal polyps has been increasing among individuals age 20 to 79, in men and women and including all races and ethnicities. CONCLUSIONS: In an analysis of a large, nationally representative sample, we found that surgery for nonmalignant colorectal polyps is common and has significantly increased over the past 14 years.

Type 2 diabetes and the risk of colorectal adenomas: Black Women's Health Study.

Evidence for the association of type 2 diabetes mellitus (DM) with colorectal neoplasms is contradictory, and African Americans have been underrepresented in the studies published to date. In a nested case-control study (1995-2009), we examined DM and insulin therapy as risk factors for colorectal adenomas in African American women enrolled in the ongoing Black Women's Health Study. From women reporting ever having undergone a gastrointestinal endoscopy, 917 cases of colorectal adenoma were compared with 2,751 controls without a colorectal polyp, matched on age and follow-up time. Cases were verified by medical record review. We used multivariable logistic regression analyses that included DM exposures and selected confounders. There were no overall associations between DM and adenoma risk or between insulin use and adenoma risk. However, DM without insulin use was inversely associated with risk of colon adenomas (odds ratio (OR) = 0.71, 95% confidence interval (CI): 0.52, 0.97) but not rectal adenomas. DM was inversely associated with adenoma risk in women older than 55 years (OR = 0.64, 95% CI: 0.44, 0.91) but not in women 55 years or younger (OR = 1.24, 95% CI: 0.81, 1.89). Future research should attempt to replicate the unexpected inverse association of DM with colon adenoma risk among older African American women.

Molecular features of colorectal hyperplastic polyps and sessile serrated adenoma/polyps from Korea.

Abundant recent data suggest that sessile serrated adenoma/polyp (SSA/P) is an early precursor lesion in the serrated pathway of carcinogenesis. It is believed that SSA/Ps develop cancer by an SSA/P-dysplasia-carcinoma sequence. Hyperplastic polyps (HPs) share some histologic and molecular characteristics with SSA/P, but it is unclear whether SSA/Ps are derived from HPs or whether they develop by a different pathogenetic pathway. Previous studies have shown that serrated polyps from Korean patients show different prevalence rates of certain molecular abnormalities compared with similar lesions from American patients, and this suggests that lifestyle and dietary factors may influence the serrated neoplasia pathway. The purpose of this study was to evaluate the molecular features of HPs and SSA/Ps, the latter both with and without dysplasia, from Korean patients and to compare the findings with similar lesions from American patients. One hundred and eleven serrated polyps, consisting of 45 HPs (30 microvesicular, 11 goblet cell, 4 mucin depleted) and 56 SSA/Ps (36 with dysplasia, 20 without dysplasia), were retrieved from the pathology files of a large medical center in Korea and 38 SSA/P from American patients were evaluated for BRAF and KRAS mutations, microsatellite instability, and hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT), hMLH1, adenomatous polyposis coli (APC), p16, methylated in tumor-1 (MINT-1), MINT2, and MINT31. Methylation of hMLH1 was performed using 2 different sets of primers. Twenty-three conventional adenomas from Korean patients were included as controls. The data were compared between polyp subtypes and between polyps in the right versus the left colon. With regard to HP, KRAS mutations were present in 31.1% of polyps and BRAF mutations in 46.7% of polyps. KRAS mutations were significantly more common in goblet cell HP and BRAF in microvesicular HP (MVHP). Methylation of MGMT, hMLH1, APC, p16, MINT1, MINT2, and MINT31 were present in 42.2%, 64.4% (and 24.4%), 37.8%, 60%, 68.9%, 51.1%, and 60% of HPs. CpG island methylator phenotype high was noted in 60% of HPs. Methylation of hMLH1, p16, MINT2, and MINT31 were more frequent in MVHPs compared with other types of HPs. In contrast, SSA/Ps showed KRAS and BRAF mutations in 12.5% and 60.7% of cases, respectively. Methylation of all tumor-related genes, except hMLH1 (23.2% using 1 type of primers) and APC (37.5%), occurred in >50% of lesions, and CpG island methylator phenotype (CIMP) high was noted in 76.8% of cases. None of the molecular findings were significantly more common in SSA/P with, versus those without, dysplasia, but only 2 of the 36 polyps with dysplasia were of the conventional adenomatous type; the remainder (34 of 36) was of the serrated type. Nevertheless, both SSA/P with conventional adenomatous dysplasia showed methylation of MGMT, APC, MINT1, and MINT31 and were CIMP high. BRAF mutations, methylation of most tumor related genes, and CIMP high occurred more frequently in HPs and SSA/Ps in the right colon, compared with the left colon. In fact, no significant differences were observed between HPs and SSPs of the right colon and HPs and SSA/Ps from the left colon. Furthermore, compared with American patients, Korean male individuals were affected more frequently than female individuals, and both BRAF mutations and hMLH1 methylation were less frequent in the latter compared with the former. We conclude that HPs and SSA/Ps in Korean patients share some, but not all, clinical and molecular characteristics to those that occur in Americans. The data support the theory that the right and left colon are biologically different with regard to susceptibility to serrated cancer, and that anatomic location (right vs. left) may be a more significant risk factor of progression than the histologic type of polyp. Our data also support the theory that right-sided MVHPs may be a precursor to SSA/P.

Asia Pacific consensus recommendations for colorectal cancer screening.

Colorectal cancer (CRC) is rapidly increasing in Asia, but screening guidelines are lacking. Through reviewing the literature and regional data, and using the modified Delphi process, the Asia Pacific Working Group on Colorectal Cancer and international experts launch consensus recommendations aiming to improve the awareness of healthcare providers of the changing epidemiology and screening tests available. The incidence, anatomical distribution and mortality of CRC among Asian populations are not different compared with Western countries. There is a trend of proximal migration of colonic polyps. Flat or depressed lesions are not uncommon. Screening for CRC should be started at the age of 50 years. Male gender, smoking, obesity and family history are risk factors for colorectal neoplasia. Faecal occult blood test (FOBT, guaiac-based and immunochemical tests), flexible sigmoidoscopy and colonoscopy are recommended for CRC screening. Double-contrast barium enema and CT colonography are not preferred. In resource-limited countries, FOBT is the first choice for CRC screening. Polyps 5-9 mm in diameter should be removed endoscopically and, following a negative colonoscopy, a repeat examination should be performed in 10 years. Screening for CRC should be a national health priority in most Asian countries. Studies on barriers to CRC screening, education for the public and engagement of primary care physicians should be undertaken. There is no consensus on whether nurses should be trained to perform endoscopic procedures for screening of colorectal neoplasia.

Ethnic differences in the anatomical location of colorectal adenomatous polyps.

The ratio of right- to left-sided colonic cancer is increasing, but data on the distribution of its usual precursor lesion, the colorectal adenoma, are contradictory. Therefore, we investigated the prevalence of right- and left-sided colorectal adenomatous polyps from January 1, 1970, to September 30, 1989, using the study design of "epidemiologic necropsy" and the autopsy files of The Johns Hopkins Hospital. Compared with the decade of the 1970's, the 1980's showed a slight decrease in the overall prevalence of right-sided adenomas (6.4 per 1,000, 95% confidence limits 4.7-8.8 vs. 5.1 per 1,000, 95% CL 3.6-6.5), but a marked decrease occurred in left-sided adenomas (11.8 per 1,000, 95% CL 9.3-14.3 vs. 6.7 per 1,000, 95% CL 4.8-8.6). As a result, the ratio of right-sided to left-sided adenomas increased from 0.55 in the 1970's to 0.77 in the 1980's. This increased ratio occurred in both sexes, although prevalences were lower in females, and in whites. Unexpectedly, blacks had a ratio of right-sided to left-sided adenomas greater than unity in both the 1970's and 1980's (1.19 vs. 1.79) due to a relatively high prevalence of right-sided adenomas (5.8 per 1,000, 95% CL 3.6-8.0 in 1970's; 5.8 per 1,000, 95% CL 3.3-8.3 in 1980's), but low prevalences of left-sided adenomas (4.9 per 1,000, 95% CL 3.0-6.8 in 1970's; 3.2 per 1,000, 95% CL 1.2-5.2 in 1980's). The overall adenoma prevalence in blacks was lower than in whites. We conclude that the right-sided predominance of colorectal adenomas in blacks suggests ethnic differences in the pathogenesis of colorectal adenomas. This observation may have important implications for secondary prevention of colorectal cancer.

Colorectal polyps in the Upper Galilee.

This study of colorectal polyps is based on 129 patients in whom 241 colorectal polyps were diagnosed and excised by colonoscopy in the Gastroenterology Unit of a hospital in the Upper Galilee, Israel, between 1 July 1984 and 30 June 1987. The male:female ratio was 2:1. Anemia was demonstrated in 7% and positive Hemoccult II test (Smith Kline, USA) in 64%. The types of polyp were 58% adenomatous, 25% hyperplastic and 15% inflammatory. Adenomatous polyps were larger than the other types (chi 2 = 13.24, P less than 0.01), and were more frequent in the left colon than inflammatory polyps (chi 2 = 4.67, P less than 0.05). The annual incidence of colorectal polyps and the percentage of colonoscopies that revealed polyps were highest for Jews of European/American origin (5.3/10,000, 26%) compared with Jews of Israeli and Asian/African origin and Arabs (2/10,000, 6%; 1.3/10,000, 12%; and 1/10,000, 9%, respectively). These data confirm findings of other investigators showing a higher incidence of colorectal polyps in European/American Jews than in other ethnic Israeli groups.

Site-specific distribution of large-bowel adenomatous polyps. Emphasis on ethnic differences.

The anatomic distribution of adenomatous polyps occurring in the large intestine of 98 consecutive patients was studied. Fifty-two of the patients were black and 46 were white. Seventy-nine percent of lesions in whites were found in the distal colon and rectum, whereas in blacks this occurred in only 47 percent. The difference was significant (P less than .01). Black patients also displayed a greater frequency of synchronous polyps and had a higher incidence of previous colorectal polyps. The findings suggest that the total colonic surveillance is essential in black patients to adequately screen for large-bowel neoplasia.

Adenomas, metaplastic polyps and other lesions of the large bowel: an autopsy survey.

Out of 1,014 large intestines examined, adenomatous polyps were encountered in 170 (16.8%) and metaplastic polyps in 67 (6.6%). Both types of polyps were more prevalent among the Chinese than the Malays and Indians. The prevalence rates corresponded to the relative risks for large bowel cancer for the respective ethnic groups. This suggests that causative factors such as dietary influence which are common to adenomatous polyps and cancer of the large bowel are operating at different levels among the different ethnic groups in Singapore. There are however, several factors between adenomatous polyp and colorectal cancer which are not congruent suggesting that the relationship between these two lesions though close is not a simple or direct one. On the other hand, the present study has shown several similarities between the epidemiological characteristics of metaplastic polyps and cancer of the large bowel. It is speculated that the causative factor(s) for metaplastic polyps may occur in association with carcinogen of the large bowel, but has an independent action. Consequently, while the metaplastic polyp may not itself be regarded as a premalignant lesion, the possibility that it may be a marker for increased risk for colon cancer is not excluded. Ulcerative colitis is rare in Singapore, and is not considered an important lesion in the pathogenesis of large bowel cancer in this country.

Adenomatous polyps and atherosclerosis: an autopsy study of Japanese men in Hawaii.

It is generally accepted that most colorectal cancers arise from adenomatous polyps and most coronary heart disease is caused by severe atherosclerosis. In order to compare the frequency of these disease precursors in men of Japanese ancestry in Hawaii, the degree of atherosclerosis of the aorta and coronary arteries was estimated by the panel method in 288 male autopsy subjects. The extent of atherosclerosis was then compared in men who did or did not have adenomatous polyps as determined at autopsy. The degree of atherosclerosis of the coronary arteries and aorta was positively and significantly related not only to the presence of adenomatous polyps, but to their size, multiplicity, and degree of atypia as well. This study suggests that shared environmental events could account for the development of severe atherosclerosis and adenomatous polyps. At the same time, it has been observed that hawaii Japanese men experience colon and rectal cancer rates higher than those of US Whites, but their coronary heart disease (CHD) rates are intermediate between the low rates of Japan and the high rates of the US white population. These differences in disease trends and differences in the serum cholesterol and fat intake of Hawaii Japanese men with CHD and colon cancer have suggested that men with these diseases represent different subsets of the westernized Japanese population. If CHD and colon cancer occur in different subsets of this population, they must stem from the accumulation of other risk factors superimposed upon the initiators of their precursor lesions.