Abnormalities of lectin histochemistry in familial polyposis coli and hereditary nonpolyposis colorectal cancer

A transformation in the composition of colonic glycoconjugates has been described in adenomas, carcinomas, and certain premalignant conditions. These changes have been detected histochemically by the labeling patterns of fluorescein-conjugated lectins, which bind specific carbohydrate structures on fixed tissue sections. This study was performed to determine whether abnormal lectin binding patterns are present in tissues from patients genetically predisposed to colonic neoplasms and whether these patterns could be used as phenotypic markers for inheritance of the genotype. Lectin staining patterns of 22 colectomy specimens from patients with familial polyposis coli (FPC) and rectal biopsy specimens from 47 patients at risk for hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndromes I and II) were compared with rectal biopsy specimens from 27 sex-matched controls. The fluorescein-conjugated lectins included the agglutinins derived from peanut, Dolichos biflorus, Ulex europeus, and wheat germ (including the succinylated derivative). Using a technique for quantitating lectin binding on the tissue sections that provided a score from 0 to 400, labeling with certain lectins was found to vary slightly as a function of age and sex. Histologically normal mucosa from patients with FPC bound significantly less wheat germ agglutinin but significantly more U. europeus and succinylated wheat germ agglutinins than controls. Adenomas and dysplastic flat mucosa from the colectomy specimens of patients with FPC showed significantly less binding with D. biflorus, succinylated wheat germ, and wheat germ agglutinins than controls. Rectal tissues from patients at risk for HNPCC were found to bind significantly less peanut agglutinin and D. biflorus agglutinin than controls. Of interest, staining of the tissues by peanut and wheat germ lectins increased as a function of patient age; the control subjects were older than the patients with familial colon cancer, which could possibly account for the observations made with these two lectins. These results provide evidence that the premalignant colonic epithelium in familial polyposis and the hereditary nonpolyposis colon cancer syndromes may be biologically different and indicate that glycoconjugate modifications are early events in the evolution of the neoplastic phenotype.     

Decentralized colonoscopic surveillance with high patient compliance prevents hereditary and familial colorectal cancer

Although colonoscopic surveillance is recommended both for individuals with known hereditary colorectal cancer (HCRC) syndromes and those with a more moderate familial colorectal cancer (FCRC) history, the evidence for the benefits of surveillance is limited and surveillance practices vary. This study evaluates the preventive effect for individuals with a family history of CRC of decentralized colonoscopic surveillance with the guidance of a cancer prevention clinic. We performed a population based prospective study of 261 patients with HCRC or FCRC, recorded in the colonoscopic surveillance registry at the Cancer genetics clinic, University Hospital of Umeå, Sweden. Colonoscopic surveillance was conducted every second (HCRC) or fifth (FCRC) year at local hospitals in Northern Sweden. Main outcome measures were findings of high-risk adenomas (HRA) or CRC, and patient compliance to surveillance. Estimations of the expected numbers of CRC without surveillance were made. During a total of 1256 person years of follow-up, one case of CRC was found. The expected numbers of cancers in the absence of surveillance was between 9.5 and 10.5, resulting in a standardized incidence ratio, observed versus expected cases of CRC, between 0.10 (CI 95 % 0.0012–0.5299) and 0.11 (CI 95 % 0.0014–0.5857). No CRC mortality was reported, but three patients needed surgical intervention. HRA were found in 5.9 % (14/237) of the initial and in 3.4 % (12/356) of the follow-up colonoscopies. Patient compliance to the surveillance program was 90 % as 597 of the planned 662 colonoscopies were performed. The study concludes that colonoscopic surveillance with high patient compliance to the program is effective in preventing CRC when using a decentralized method for colonoscopy surveillance with the guidance of a cancer prevention clinic.     

Evaluation of an online family history tool for identifying hereditary and familial colorectal cancer

Identifying a hereditary colorectal cancer (CRC) syndrome or familial CRC (FCC) in a CRC patient may enable the patient and relatives to enroll in surveillance protocols. As these individuals are insufficiently recognized, we evaluated an online family history tool, consisting of a patient-administered family history questionnaire and an automated genetic referral recommendation, to facilitate the identification of patients with hereditary CRC or FCC. Between 2015 and 2016, all newly diagnosed CRC patients in five Dutch outpatient clinics, were included in a trial with a stepped-wedge design, when first visiting the clinic. Each hospital continued standard procedures for identifying patients at risk (control strategy) and then, after a predetermined period, switched to offering the family history tool to included patients (intervention strategy). After considering the tool-based recommendation, the health care provider could decide on and arrange the referral. Primary outcome was the relative number of CRC patients who received screening or surveillance recommendations for themselves or relatives because of hereditary CRC or FCC, provided by genetic counseling. The intervention effect was evaluated using a logit-linear model. With the tool, 46/489 (9.4%) patients received a screening or surveillance recommendation, compared to 35/292 (12.0%) in the control group. In the intention-to-treat-analysis, accounting for time trends and hospital effects, this difference was not statistically significant (p?=?0.58). A family history tool does not necessarily assist in increasing the number of CRC patients and relatives enrolled in screening or surveillance recommendations for hereditary CRC or FCC. Other interventions should be considered.     

Diagnosing hereditary colorectal cancer

Although progress in the treatment of patients with colorectal cancer (CRC) has resulted in improved median survival, most patients with metastatic CRC still die of their disease, and essentially all patients with early-stage disease must undergo surgical resection and subsequently face the possibility of adjuvant chemotherapy. As effective screening and prevention strategies for CRC have been developed, identification of individuals with a hereditary predisposition to developing CRC is especially important and provides the opportunity to reduce disease burden in this high-risk population. Increased awareness and improved diagnostic techniques for hereditary CRC syndromes have facilitated more frequent diagnosis and management of a small number of highly penetrant syndromes within families. However, known high-penetrance genetic predisposition syndromes account for a minority of all familial CRC, leaving much of the genetic basis of CRC unexplained. Recent advances in high-throughput genotyping have made possible genome-wide association studies, which have identified novel genetic variants associated with modest increases in CRC risk. While these associations have helped to identify potentially important pathways in CRC carcinogenesis, at the current time, the clinical use of such genetic risk variants in colon cancer risk stratification remains limited.     

hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer

The pattern of hMLHI and hMSH2 mutations was assessed to identify the genetic correlation between hereditary gastric and colorectal cancers. Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33). In the CG group, three were included in AMS + and six in AMS- criteria. Peripheral blood was obtained from them to detect hMLHI and hMLH2 mutations using PCR-SSCP analysis and direct sequencing. The incidence of mutations was 9.4% in the FG group, 54.5% in the CG group, 31.6% in the HS group, and none in the SG group. The incidence, type, and number of the mutation were not different between the CG and HS groups. Thirty-four different mutations included 19 in hMLH1 and 15 in hMSH2. Gastric cancer was the most common extracolonic malignancy in HNPCC and suspected HNPCC families (9/28, 32.1%). The hMLH1 or hMSH2 mutation occurred in seven of 10 families with AMS+, whereas it occurred in four of 18 with AMS- (70% vs. 22.2%, P = .013). Five mutations in the hMLH1 and six mutations in the hMSH2 were exclusively found in families with gastric cancer. All three mutations in the FG group were in hMLHI and there was no mutation in their healthy family members. This study demonstrates that some familial clustering type of gastric cancer appears to be associated with hMLHI mutations thereby indicating a difference from the hereditary gastric cancer studies previously reported. In addition, hMLHI and hMSH2 mutations may impact the gastric cancer carcinogenesis in HNPCC or suspected HNPCC.     

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation‐negative familial ovarian cancers

BACKGROUND:

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC‐related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

METHODS:

Seventy‐seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC‐associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.

RESULTS:

None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious.

CONCLUSIONS:

HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing. Cancer 2009. © 2009 American Cancer Society.     

Undefined familial colorectal cancer

Colorectal cancer (CRC), one of the most common cancers of the world, is actually a spectrum of several subtypes, with different molecular profiles, clinico-pathological characteristics and possibly separate pathways of progression. It is estimated that in approximately 25%-35% of cases, a familial component exists, so they are classified as familial CRC (fCRC). However the known hereditary CRC syndromes justify only up to 5%. The rest are attributed to some inherited genetic predisposition passed to offspring through low-penetrance genes, which in the proper environmental setting can bring on tumorigenesis. Furthermore, part of the familial clustering may be attributed to chance. Because of the complexity regarding the etiology of CRC, the clinician is sometimes faced with obscure patient data, and cannot be sure if they are dealing with fCRC or sporadic CRC. The elucidation of what is going on with the as yet "undefined" portion of CRC will aid not only in the diagnosis, classification and treatment of CRC, but more importantly in the proper adjustment of the screening guidelines and in genetic counselling of patients.     

Genetics of hereditary colorectal cancer

Genetic factors can dramatically influence the risk of colorectal cancer, and the molecular bases of many hereditary colorectal cancer syndromes, including familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and hereditary nonpolyposis colorectal cancer (HNPCC) have been elucidated. Additional syndromes continue to be defined as new genes, including MYH , are linked to the development of colonic polyps and cancer. The risks of colorectal cancer are variable and depend on the specific germline alterations. Some mutations are associated with a 100% lifetime risk of developing cancer, while others are associated with only a mild increase in risk. Although there are overlapping clinical features in many of these syndromes, they can be distinguished by the age at cancer diagnosis, inheritance pattern, number and distribution of polyps, specific histologic features of the cancers, and the presence of distinctive extracolonic features. The introduction and refinement of genetic testing has provided a new and invaluable tool for the diagnosis and assessment of cancer risk for suspected cases of hereditary colon cancer.     

Screening for familial and hereditary prostate cancer

Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome‐wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies.     

Genetic alteration in hereditary colorectal cancer

Colorectal cancer is a major cause of morbidity and mortality. Both genetic and environmental factors contribute to cancer aetiology. About 15-20% of all colorectal cancers are familial. Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counselling. Genetic testing for hereditary forms of colorectal cancer can confirm or reject diagnoses at the molecular level, determine surveillance intervals for at-risk persons, decrease the cost of surveillance by risk stratification, aid in surgical and chemoprevention decision-making, and help patients in family and career planning. This paper reviews the genetics behind genes and molecular study of the hereditary colorectal cancer. This may help the medical professionals especially internists, gastroenterologists, and oncologists to update their knowledge in this field.     

家族遗传性前列腺癌研究进展

前列腺癌在我国的发病率逐年上升,且具有高度遗传性。随着测序技术的发展及相关研究的进展,家族遗传性前列腺癌获得更加深入的认识。越来越多的基因突变、单核苷酸多态性和拷贝数变异等被证实与前列腺癌的发生发展有着密不可分的关系,针对这些可能的致病因素开发出多种药物,并且疗效已为临床试验所证实,对家族遗传性前列腺癌特征的描述也为临床管理带来了新的思考。本文总结现有文献,针对家族遗传性前列腺癌的特点、遗传基础、治疗、检测及筛查进行综述。      

家族遗传性前列腺癌研究进展

前列腺癌在我国的发病率逐年上升,且具有高度遗传性。随着测序技术的发展及相关研究的进展,家族遗传性前列腺癌获得更加深入的认识。越来越多的基因突变、单核苷酸多态性和拷贝数变异等被证实与前列腺癌的发生发展有着密不可分的关系,针对这些可能的致病因素开发出多种药物,并且疗效已为临床试验所证实,对家族遗传性前列腺癌特征的描述也为临床管理带来了新的思考。本文总结现有文献,针对家族遗传性前列腺癌的特点、遗传基础、治疗、检测及筛查进行综述。      

Sulindac inhibits beta-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients.

Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-beta-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, beta-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, beta-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and sulindac. Intensity of membranous beta-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits beta-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.     

Colonoscopy and chromoscopy in hereditary colorectal cancer syndromes

With hereditary colorectal cancer prevention studies it is difficult to demonstrate reduced mortality. Large populations are needed with well characterized genetics followed over a long period of time. Those studies do exist for standard white light colonoscopy surveillance in Lynch syndrome, but not for newer technologies including chromoscopy. For these newer technologies adenoma detection rate becomes the stand-in for mortality, and the assumption is made that surveillance efficacy impacts cancer occurrence. Though well-designed and important work exists in this area, the data do not support firm conclusions regarding the use of chromoscopy in Lynch syndrome.     

A new hereditary colorectal cancer network in the Middle East and eastern mediterranean countries to improve care for high-risk families

Colorectal cancer (CRC) has a very high incidence in the western world. Data from registries in the Middle East showed that the incidence of CRC is relatively low in these countries. However, these data also showed that CRC incidence has increased substantially over the past three decades and that a high proportion of cases are diagnosed at an early age (<50 years). In view of these findings, more attention should be paid to prevention. Because of the often limited financial resources, focused screening of individuals with hereditary CRC, in particular those with Lynch syndrome, appears to be the most cost-effective strategy. During recent meetings of the Palestinian Society of Gastroenterology and the Mediterranean Task force for Cancer Control (MTCC) in Jericho, and the Patient’s Friends Society of Jerusalem in Hebron the issue of hereditary CRC in the Middle East was discussed and the idea was conceived to establish a network on hereditary colorectal cancer (HCCN-ME) with the goal of improving care for high-risk groups in the Middle East and (Eastern) Mediterranean Countries.     

Sulindac treatment in hereditary non-polyposis colorectal cancer

Non-steroidal anti-inflammatory drugs, e.g. sulindac have been extensively studied for chemoprevention in familial adenomatous polyposis, but not in hereditary non-polyposis colorectal cancer (HNPCC). We evaluated these effects in HNPCC using surrogate end-points for cancer risk. In a randomised double-blind cross-over study, 22 subjects (9 female; age 30-66 years, mean 44), all ascertained or probable mutation carriers for HNPCC, were included. Sulindac 150 mg b.i.d. and placebo were given for 4 weeks each, with 4 weeks in between, with biopsies taken from ascending, transverse and sigmoid colon and rectum by colonoscopy after both periods. Proliferation was determined by Ki-67 staining and apoptosis by staining of cytokeratin 18 cleavage products. Expression of cyclins B1, D3 and E and p21, p27, bax, bcl2 and cox-2 was studied immunohistochemically. Proliferation was higher during sulindac treatment than drug placebo treatment in ascending and transverse colon, but not in sigmoid and rectum. Apoptosis was not affected. Besides an increase in cyclin D3, no differences were found in expression of regulating proteins in the proximal colon. CONCLUSION: Sulindac induces an increase in epithelial cell proliferation in the proximal colon of subjects with HNPCC. Since colorectal cancer predominantly arises in the proximal colon in HNPCC, these results cast doubts on the potential chemopreventive effects of sulindac in HNPCC.     

Current approaches in hereditary nonpolyposis colorectal cancer

This article emphasizes the central role of tumor-based testing for microsatellite instability followed by performance of genetic counselor-driven germline mutation testing in hereditary nonpolyposis colorectal cancer (HNPCC). Suitably aggressive colorectal neoplasm surveillance is shown to be critical. Limitations of the evidentiary base for extracolonic screening are conceded, with some cautious suggestions for possible strategies notwithstanding the lack of data. Advances in chemoprevention have been made in both familial adenomatous polyposis (clinical trial data favoring eicosapentaenoic acid) and HNPCC (controversial aspirin data). For various reasons, however, no agent or combination of agents has yet come into routine use in either condition, with further trials underway or being designed for both conditions.     

Prolonged survival in hereditary nonpolyposis colorectal cancer

We compared the survival between 46 patients with hereditary nonpolyposis colorectal cancer (HNPCC) and 1185 cases with sporadic colorectal cancer, who underwent a resection for the disease between 1972 and 1995. In a univariate analysis, the survival correlated well with stage, curability, size and the presence of HNPCC. Patients with HNPCC had a longer survival than those with sporadic colorectal cancer (P=0.0277). A multivariate analysis suggested that stage, curability, age, and HNPCC were the effective combination of factors predictive of survival. The above findings are thus expected to have a major influence on the evaluation of clinical trials in patients with colorectal cancer.     

Surveillance improves survival of colorectal cancer in patients with hereditary nonpolyposis colorectal cancer

Some patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome develop carcinoma despite surveillance. The aim of this study was to determine whether survival was greater in colorectal cancer (CRC) cases detected by surveillance than in patients who had disease diagnosed on the basis of symptoms. All 150 CRC cases detected in 57 HNPCC families over the last 15 years were divided into two groups depending on whether they had been included in the surveillance program (n = 35) or not (n = 115). The stage distribution of the tumors in the group that underwent surveillance (Dukes' A, 50%; B, 35%; C, 15%; D, 0%) was significantly more favorable (P < .001) than in the group without surveillance (Dukes' A, 17%; B, 50%; C, 16%; D, 17%). CRC-specific 10-year survival was 93% in the surveillance group, significantly better than the 68% in the nonsurveillance group (P < .02). The overall survival did not differ significantly between the two groups despite a tendency in favor of the surveillance group. Colonoscopic surveillance enables early detection of CRC in HNPCC and reduces CRC mortality.