A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history

Objectives: Adenomatous polyposis of the colon is often secondary to an inherited mutation in adenomatous polyposis coli (APC) gene, however, approximately one third of patients have no family history of the disease. We studied the phenotype and genotype of adenomatous polyposis in patients without a family history. Methods: A cohort of 57 unrelated adenomatous polyposis patients were evaluated. Seventeen patients with no family history were compared with 40 patients who had a positive family history of the disease. Family history and medical records were collected and analyzed. Germline APC and Mut Y homologue (MYH) testing was undertaken. Results: Patients without a family history were diagnosed with polyposis at an older age (41 years vs. 32 years) and presenting more frequently with symptoms (76 vs 20, P < 0.05). The number of colonic polyps and frequency of extracolonic manifestation associated with adenomatous polyposis did not differ between the two groups. APC mutations were detected less frequently among patients without a family history of the disease (4 out of 17 vs 25 out of 40, P=0.007), even among those with greater than 100 colorectal adenomas (4 out of 12 versus 21 out of 29, P=0.03). One homozygous MYH mutation carrier (G382D) was detected among the six patients without a family history and without a germline APC mutation who were tested. Conclusions: Adenomatous polyposis patients without a family history are usually diagnosed with symptoms, and at a later age. Phenotypically, they are similar to those with a family history. However, germline APC mutations are detected far less frequently in patients without a family history. A small percentage of these cases may be secondary to biallelic germline MYH mutations.     

Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients

In 10-30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli (APC) gene can be identified (APC mutation-negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to (i) assess the MYH mutation carrier frequency among Swiss APC mutation-negative patients and (ii) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation-negative polyposis patients. Seventy-nine unrelated APC mutation-negative Swiss patients with either classical (n=18) or attenuated (n=61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance (n=45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly (p<0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation-negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: (i) presence of classical or attenuated polyposis coli, (ii) absence of a pathogenic APC mutation, and (iii) a family history compatible with an autosomal recessive mode of inheritance.     

The Mutation Spectrum and Two Novel Point Mutations in the APC Gene in Vietnamese Patients with Familial Adenomatous Polyposis

Background: Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is point mutation, while deletion mutation is much less frequent. The current study was conducted to investigate the mutation spectrum of the APC gene in Vietnamese FAP patients. Methods: Patients with the clinical diagnosis of FAP on colorectal endoscopy were screened for mutations in the APC gene using Sanger sequencing. Those who exhibited no point mutation subsequently underwent MLPA assay to detect deletion and duplication mutations. Besides, the relatives of patients with mutated APC genes were recruited for detecting carrier status. Results: Sixty-three patients with clinical colorectal polyposis were recruited. Mutations in the APC gene were detected in 26/63 patients (41.3%). Genetic analysis of 105 asymptomatic relatives of these 26 patients found mutations in the APC gene in 55 individuals (52.4%). Conclusion: We successfully established the APC gene mutation spectrum in Vietnamese FAP patients for the first time. Of importance, we discovered two novel point mutations in the APC gene. The high prevalence of carrier status in asymptomatic family members of patients with mutation emphasizes the crucial role of appropriate genetic screening for early diagnosis, surveillance, and preventive measurements.     

Somatic Mutation of the APC Gene in Thyroid Carcinoma Associated with Familial Adenomatous Polyposis

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 20-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.     

Genotype and phenotype of patients with both familial adenomatous polyposis and thyroid carcinoma

The incidence of thyroid carcinoma in familial adenomatous polyposis (FAP) is thought to be 1%–2%, with the majority of cases being female. We have investigated the phenotype and genotype of 16 patients with FAP associated thyroid carcinoma. Among 1194 FAP patients studied in two high risk registries in North America (Familial Gastrointestinal Cancer Registry, Toronto and University California, San Francisco), 16 (1.3%) unrelated patients with FAP associated thyroid cancers were identified. Adenomatous polyposis coli (APC) gene testing was performed in 14 of the 16 cases. The average age of diagnosis for FAP and thyroid carcinoma was 29 years (range 17–52 years) and 33 years (range 17–55 years), respectively. All FAP patients except 1 had more than 100 colonic adenomas. Extracolonic manifestations, beside thyroid cancer, were presented in 81% (n = 13) of the patients, including gastric and duodenal polyps, desmoid tumor, osteoma, epidermoid cyst, sebaceous cyst and lipoma. Colorectal cancer was diagnosed in 38% (n = 6) of the patients. The pathology of the FAP associated thyroid cancer was predominantly papillary carcinoma. Germline mutations were identified in 12 of 14 patients tested. Mutations proximal to the mutation cluster region (1286–1513) were detected in 9 cases. Thyroid cancer in our FAP population was rare, predominantly in females and showed papillary carcinoma histology. Additionally, thyroid cancer in our patients occurred in the setting of classic FAP phenotype. Germline mutations were located predominantly outside the APC mutation cluster region. This revised version was published online in August 2006 with corrections to the Cover Date.     

Gonadal mosaicism and familial adenomatous polyposis

De novo mutations in the adenomatous polyposis coli (APC) gene are estimated to constitute approximately 25% of familial adenomatous polyposis (FAP) cases. A small percentage of these arise in the mosaic form, affecting only a subset of cells in the affected individual. A family is described here whereby an unaffected mother with no detectible mutation in APC, transmitted the identical APC c.4729G>T (p.Glu1577X) mutation to two children. A third child, with the same APC allelic haplotype received a normal APC allele, suggesting that the mutation originated in the gonadal tissues of the mother. These results underscore the utility of mutation-specific genetic testing for the parents and siblings of a proband of an adult-onset disease, even if the proband appears to have a de novo mutation. Parents who test negative for the mutation should be counseled about the possibility of having another affected child due to gonadal mosaicism.     

APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis

Correlations between germline APC mutation sites and colorectal pathophenotypes, as evaluated by the direct count of adenomas at colectomy, were investigated analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon 208) and 14 frame-shift or non-sense APC mutations (codons 232, 367, 437, 623, 876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation at codon 208 was associated with a relatively mild colorectal pathophenotype. The mutation at codon 367, subject to alternative splicing, was associated with attenuated FAP. The mutation at codon 1309 was associated with the profuse colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted functional effects of the mutation. The most severe colorectal pathophenotype was significantly associated with the truncating mutation at codon 1309, which is located downstream to the I beta-catenin binding domain but upstream II beta-catenin-binding domain. Mutations between codons 867 and 1114, which affect the I beta-catenin binding domain, as well as mutations occurring in exons 6 and 9, predicted to result in null alleles, were associated with a less severe colorectal pathophenotype. Overall, the highest number of adenomas was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observed in the left colon, followed by the right colon, sigma, transverse colon and rectum. Colorectal carcinomas, observed in only five patients, were all in the left colon.     

Analysis of Small Fragment Deletions of the APC gene in Chinese Patients with Familial Adenomatous Polyposis,a Precancerous Condition

Background: : Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease mainly causedby mutations of the adenomatous polyposis coli (APC) gene with almost complete penetrance. These colorectalpolyps are precancerous lesions that will inevitable develop into colorectal cancer at the median age of 40-yearold if total proctocolectomy is not performed. So identification of APC germline mutations has great implicationsfor genetic counseling and management of FAP patients. In this study, we screened APC germline mutationsin Chinese FAP patients, in order to find novel mutations and the APC gene germline mutation characteristicsof Chinese FAP patients. Materials and Methods: The FAP patients were diagnosed by clinical manifestations,family histories, endoscope and biopsy. Then patients peripheral blood samples were collected, afterwards,genomic DNA was extracted. The mutation analysis of the APC gene was conducted by direct polymerasechain reaction (PCR) sequencing for micromutations and multiplex ligation-dependent probe amplification(MLPA) for large duplications and/or deletions. Results: We found 6 micromutations out of 14 FAP pedigrees,while there were no large duplications and/or deletions found. These germline mutations are c.5432C>T(p.Ser1811Leu), two c.3926_3930delAAAAG (p.Glu1309AspfsX4), c.3921_3924delAAAA (p.Ile1307MetfsX13),c3184_3187delCAAA(p.Gln1061AspfsX59) and c4127_4126delAT (p.Tyr1376LysfsX9), respectively, and alldeletion mutations resulted in a premature stop codon. At the same time, we found c.3921_3924delAAAA andtwo c.3926_3930delAAAAG are located in AAAAG short tandem repeats, c3184_3187delCAAA is located in theCAAA interrupted direct repeats, and c4127_4128 del AT is located in the 5’-CCTGAACA-3’ ,3’-ACAAGTCC-5palindromes (inverted repeats) of the APC gene. Furthermore, deletion mutations are mostly located at condon1309. Conclusions: Though there were no novel mutations found as the pathogenic gene of FAP in this study,we found nucleotide sequence containing short tandem repeats and palindromes (inverted repeats), especiallythe 5 bp base deletion at codon 1309, are mutations in high incidence area in APC gene.     

Genetic testing for young-onset colorectal cancer: case report and evidence-based clinical guidelines

BACKGROUND: Young-onset colorectal cancer is clinicopathologically different from older-onset colorectal cancer and tends to occur in patients with hereditary germline conditions such as Lynch syndrome and familial adenomatous polyposis. CASE REPORT.: We describe the case of a 44-year-old man with a paternal history of colon polyps, a personal 2-year history of hematochezia, and a diagnosis of rectal cancer. Further clinical evaluation of the patient at our institution determined the cancer to be stage IIIA. The patient underwent genetic counseling and testing, which indicated he was negative for the most common familial cancer syndromes. After treatment with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, the patient has done well. We review the hereditary cancer syndromes and genetic tests to consider for patients with early-onset colorectal cancer. CONCLUSIONS: This case underscores the importance of following cancer-screening guidelines.     

Attenuated familial adenomatous polyposis (AFAP): a review of the literature

Over the last decade, a subset of familial adenomatous polyposis(FAP) patients with a milder course of disease termed attenuated familial adenomatous polyposis (AFAP) has been described. AFAP is not well-defined as a disease entity – the reports on AFAP are largely casuistic or only deal with a few kindreds – and the diagnostic criteria and methods of investigation differ markedly. The true incidence and frequency of AFAP is not known. The mutations in APC associated with AFAP have mainly been detected in three parts of the gene: in the 5′ end (the first five exons), in exon 9 and in the distal 3′ end. The main features of AFAP are 100 or less colorectal adenomas with a tendency to rectal sparing, a delay in onset of adenomatosis and bowel symptoms of 20–25 years, a delay in onset of colorectal cancer (CRC) of 10–20 years and death from CRC of 15–20 years, and although the lifetime penetrance of CRC appears to be high, CRC does not seem to develop in nearly all affected patients. A more limited expression of the extracolonic features is seen, but gastric and duodenal adenomas are frequently encountered. Colonoscopy is preferred to sigmoidoscopy, should begin at the age of 20–25 years and no upper age limit of stopping surveillance is justified. Regular esophago-gastro-duodenoscopy (EGD) is recommended. Until further research has provided us with a more substantiated knowledge about AFAP changes in current surveillance and treatment are not recommended. Prophylactic colectomy with ileorectal anastomosis (IRA) is recommended in most patients.     

FAP associated thyroid carcinoma in mother and her daughter

A 21 year-old Japanese female was referred to the hospital for evaluation of a mass in her neck. Cytologic samples obtained through fine needle aspiration (FNA) material from the mass showed pseudopapillary or sheet-like clusters. The cells had oval nuclei and columnar cytoplasms. Nuclear groove and intranuclear inclusions were scarcely seen. The cells had a cribriform or solid pattern, unlike cells in papillary thyroid carcinoma. This distinct cytological appearance is thought to belong to FAP (familial adenomatous polyposis)-associated thyroid cancer. The patient was diagnosed with FAP associated papillary thyroid carcinoma. FAP was confirmed by colonoscopy. Her mother, 48 years old, also detected an anterior neck swelling at the time of her daughter's admission. At the age of ten, the mother had undergone total colectomy because of FAP. FNA of the mass demonstrated the same cytological appearance as from her daughter's tumor. Total thyroidectomy was performed. Gross and microscopic appearances of the tumor was similar in mother and daughter. We believe it is possible to detect FAP through FNA cytology of thyroid tumors if pathologists are aware of the unique cytohistological features of throid tumor cells in FAP.     

Difference in characteristics of APC mutations between colonic and extracolonic tumors of FAP patients: variations with phenotype

To clarify the differences in characteristics of adenomatous polyposis coli (APC) mutations between colorectal tumors from various phenotypes of familial adenomatous polyposis (FAP) and between colorectal and extracolonic tumors, we analyzed APC mutations in 86 colorectal tumors from FAP patients including profuse, sparse and attenuated types, 23 sporadic colorectal tumors and 40 FAP extracolonic tumors including duodenal, gastric and desmoid tumors. In all tumors, 1 allele of the truncated APC gene retained armadillo repeats, 15-amino-acid (aa) repeats and various numbers of 20-aa repeats, but lacked SAMP repeats, as a result of germline and somatic mutations. Regarding 20-aa repeats, the truncated APC gene retained 1 repeat due to allele loss in 96% (27/28) of colorectal tumors from profuse-type FAP, 69% (36/52) of sparse-type retained 2 repeats due to somatic mutation, and 100% (6/6) of attenuated-type retained 2 or 3 repeats due to the third or second hit. In sporadic colorectal tumors 74% (17/23) retained 1 or 2 repeats. The truncated APC gene retained 3 repeats in 88% (7/8) of FAP duodenal tumors, 100% (26/26) of gastric tumors retained 2 or 3 repeats and 83% (5/6) of desmoid tumors retained 2 repeats. These data suggest that the number of beta-catenin downregulating 20-aa repeats in truncated APC gene associated with colorectal tumorigenesis is different in profuse, sparse and attenuated types of FAP, and that the association with tumorigenesis is also different between colorectal and extracolonic tumors.     

Genetic analysis of the APC gene regions involved in attenuated APC phenotype in Israeli patients with early onset and familial colorectal cancer

The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1-5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis.     

Colon Cancer Prevention by Detection of APC Gene Mutation in a Family with Attenuated Familial Adenomatous Polyposis

Background: Genetic mutation is a significant factor in colon CA pathogenesis. Familial adenomatous polyposis(FAP) is an autosomal dominant hereditary disease characterized by multiple colorectal adenomatous polypsaffecting a number of cases in the family. This report focuses on a family with attenuated familial adenomatouspolyposis (AFAP) with exon 4 mutation, c.481C>T p.Q161X of the APC gene. Methods: We analyzed 20 membersof a family with AFAP. Clinical and endoscopic data were collected for phenotype determination. Genetic analysiswas also performed by direct sequencing of the APC gene. Result: Five patients with a phenotype of AFAP werefound. Endoscopic polyposis was demonstrated among the second generation with genotype mutation of thedisease (age > 50 years) consistent with delayed phenotypic adenomatous polyposis in AFAP. APC gene mutationwas identified in exon 4 of the APC gene, with mutation points of c.481C>T p.Q161X. Laparoscopic subtotalcolectomy was performed to prevent carcinogenesis. Conclusion: A family with attenuated familial adenomatouspolyposis of APC related to exon 4 mutation, c.481C>T p.Q161X, was reported and the phenotypic finding wasconfirmed by endoscopic examination. Genetic mutation analysis might be advantageous in AFAP for longterm colon cancer prevention and management due to subtle or asymptomatic phenotype presentation in earlyadulthood.     

Meat and Fish Consumption, APCGene Mutations and hMLH1 Expression in Colon and Rectal Cancer: a Prospective Cohort Study (The Netherlands)

Objective:The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. Methods:The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer patients on whom case-cohort analyses (subcohort n = 2948) were performed. Results:Total meat consumption was not associated with the endpoints studied. Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96–2.71, p-trend = 0.04 and 1.58, 95% CI 1.10–2.25, p-trend = 0.01, respectively). Consumption of other meat (horsemeat, lamb, mutton, frankfurters and deep-fried meat rolls) was associated with an increased risk of rectal cancer without a truncating APC mutation (RR intake versus no intake 1.79, 95% CI 1.10–2.90). No associations were observed for meat consumption and tumours lacking hMLH1 expression. Conclusions:Our data indicate that several types of meat may contribute differently to the aetiology of colon and rectal cancer, depending on APC mutation status but not hMLH1 expression of the tumour.     

胃癌患者组织中miR-497、APC的表达及其与预后的相关性

目的:探究胃癌患者组织中微小RNA-497（miR-497）、腺瘤样息肉蛋白（APC）的表达水平及其与预后的相关性。方法:选取2013年1月至2015年1月本院收治的胃癌患者67例作为研究对象,术中留取患者胃癌组织及癌旁组织。采用实时荧光定量PCR（qRT-PCR）技术检测组织中miR-497、APC mRNA表达水平,采用免疫组织化学染色法检测组织中APC蛋白表达水平,采用Kaplan-Meier法分析不同miR-497、APC表达水平患者生存情况。采用Logistic回归分析胃癌患者预后不良的影响因素。结果:胃癌组织中miR-497、APC mRNA表达水平及APC蛋白高表达率均明显低于癌旁组织（P＜0.05）。与miR-497、APC蛋白高表达患者比较,miR-497、APC蛋白低表达患者中T3-T4浸润深度、TNM分期Ⅲ-Ⅳ期、淋巴结转移比例均明显升高（P＜0.05）;APC蛋白高表达与低表达患者高、中分化与低分化比例比较,差异有统计学意义（P＜0.05）。低分化、T3-T4浸润深度、TNM分期Ⅲ-Ⅳ期、淋巴结转移为胃癌患者预后不良的独立危险因素（P＜0.05）。miR-497、APC蛋白低表达患者5年累积生存率明显低于miR-497、APC蛋白高表达患者（P＜0.05）。胃癌组织中miR-497与APC mRNA表达水平呈正相关（P＜0.05）,但相关性较弱。胃癌组织中miR-497、APC mRNA表达水平对胃癌患者不良预后诊断的曲线下面积分别为0.766、0.816,均明显低于二者联合检测曲线下面积的0.915（P＜0.05）。结论:胃癌组织中miR-497、APC表达水平明显降低,与肿瘤浸润深度加深、分化程度降低、TNM分期升高、淋巴结转移及患者生存率低有关,二者联合对胃癌患者不良预后的诊断价值最高。     

Familial adenomatous polyposis at the Tel Aviv Medical Center: demographic and clinical features

Familial adenomatous polyposis (FAP) is an uncommon, but widespread genetic disorder that develops multiple colonic adenomatous polyps and, if untreated, can lead to large bowel cancer. Little is known about its occurrence and characteristics in the Israeli population. Aims: To evaluate FAP prevalence, phenotypic manifestations and compliance for diagnosis and follow-up in our registry. Methods: Since 1993 approximately one-half of FAP patients in Israel have been seen and followed-up by us before and/or after colectomy. They and their families were encouraged to have mutation analysis, genetic and/or endoscopic screening. Results: 37 pedigrees were identified, including 2 non-Jewish. The Jewish ethnic distribution was similar to that of the general population and the point prevalence rate estimated as 28.4/one million Jewish inhabitants. There were 461 first-degree relatives at-risk for FAP. Genetic screening was completed and successful in 28 pedigrees (87.5%), and 73 FAP patients entered the registry. Marked intra-familial phenotypic variations with minimal disease manifestation were noted in 11 patients belonging to 4 pedigrees. Cancer occurred in 15.1% (11 patients), in 10 before FAP diagnosis or during follow-up elsewhere, but one non-compliant patient developed duodenal cancer. One other patient died from a massive, neglected, intra-abdominal desmoid. Compliance for evaluation and follow-up of pedigree members and individual FAP patients was inadequate in 29% and 27%, respectively. Conclusions: FAP occurs in the Israeli Jewish population at the expected rate, but is inadequately recognized in non-Jews. The inadequate compliance for screening and post-surgical follow-up needs to be addressed by educating the public, health care workers and Health Insurers.