Deficiency of Adenomatous Polyposis Coli protein in sporadic colorectal adenomas and its associations with clinical phenotype and histology

AIM： To evaluate the frequency of the loss of the Adenomatous Polyposis Coil （APC） protein and to compare the APC status with the characteristics of colorectal adenomas. METHODS： Immunohistochemical analysis of the APC protein was performed on 118 adenomas and the results were compared with parameters of malignant potential, location of adenomas, macroscopic appearance and age of the patients. RESULTS： A complete loss of the APC protein was found in 28 （24%） adenomas, while 90 （76%） were APC positive. The mean size of adenomas was 13.5± 14.2 mm （95% CI 10.5-16.5） in APC-positive, and 13.8 ±15.5 mm （95% CI 7.8-19.8） in APC-negative adenomas （P = 0.364）. Statistical analysis revealed no difference between APC-positive and negative adenomas as to the histological type （P = 0.327） and grade of dysplasia （P =0.494）. We found that even advanced adenomas did not differ in their APC status from the non-advanced tumors （P = 0.414）. Finally, no difference was found when the location （P = 0.157）, macroscopic appearance （P = 0.571） and age of patients （P = 0.438） were analysed and compared between both APC positive and negative adenomas. CONCLUSION： Most adenomas expressed full-length APC protein, suggesting that protein expression is not a reliable marker for assessment of APC gene mutation. Complete loss of APC protein did not influence morphology, location, or appearance of adenomas, nor was it affected by the patient＇s age.

Aspirin-induced long-term tumor remission in hepatocellular carcinoma with adenomatous polyposis coli stop-gain mutation:A case report

BACKGROUND Targeted therapy based on pathway analysis of hepatitis B-related hepatocellular carcinoma(HCC)may be a promising remedy.CASE SUMMARY The present case involved an advanced hepatocellular carcinoma(HCC)patient who did not receive local regional therapy and was intolerant to sorafenib.Total RNA extracted from the patient’s tumor tissue was used to obtain the gene mutation profile.The c.3676A>T and c.4402A>T stop-gain mutations in adenomatous polyposis coli(APC)were the most prevalent(42.2%and 35.1%,respectively).MutationMapper analysis indicated that the functional domain of APC was lost in the two APC mutant genes.APC is a major suppressor of the Wnt signaling pathway.Thus,the Wnt pathway was exclusively activated due to APC dysfunction,as other elements of this pathway were not found to be mutated.Aspirin has been reported to suppress the Wnt pathway by inducingβ-catenin phosphorylation through the activation of glycogen synthase kinase 3 beta via cyclooxygenase-2 pathway inhibition.Therefore,aspirin was administered to the patient,which achieved four years of disease control.CONCLUSION Exclusive mutations of APC of all the Wnt pathway elements could be a therapeutic target in HCC,with aspirin as an effective treatment option.

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a micromutation detection rate of 64.3%(9/14),including 6 frameshift mutations(66.7%),1 nonsense mutation(11.1%)and 2 splicing mutations(22.2%).Large fragment deletions were detected by MLPA in 2 families.The total mutation detection rate of micromutations and large fragment deletions was 78.6%(11/14).CONCLUSION:The detection rate of APC gene germline mutation can be improved by direct sequencing combined with MLPA large fragment deletion detection.

Attenuated adenomatous polyposis of the large bowel: Present and future

Attenuated adenomatous polyposis(AAP) is a poorly understood syndrome, that can be defined as the presence of 10-99 synchronous adenomas in the large bowel, and it is considered a phenotypic variant of familial adenomatous polyposis(FAP). This definition has the advantage of simplicity, but it may include sporadic multiple adenomas of the large bowel at an extreme, or FAP cases on the other side. AAP shows a milder phenotype than FAP, with an older age of onset of adenomas and cancer, and less frequent extracolonic manifestations. AAP may be diagnosed as a single case in a family or, less frequently, it may be present in other family members, and it shows distinct pattern of inheritance. In less than 50% of cases, it may be caused by adenomatous polyposis coli(APC) or MUTYH mutations, referred to as APC-associated polyposis, inherited as an autosomal dominant trait, or MUTYH-associated polyposis, which shows an autosomal recessive mechanism of inheritance, respectively. Surveillance should rely on colonoscopy at regular intervals, with removal of adenomas and careful histological examination. When removal of polyps is not possible or advanced lesions are observed, the surgical approach is mandatory, being subtotal colectomy with ileo-rectal anastomosis the treatment of choice. Studies on this syndrome are lacking, and controversies are still present on many issues, thus, other clinical and genetic studies are requested.

Rare combination of familial adenomatous polyposis and gallbladder polyps

Familial adenomatous polyposis is associated with a high incidence of malignancies in the upper gastrointestinal tract (particularly ampullary adenocarcinomas). However, few reports have described a correlation between familial adenomatous polyposis and gallbladder neoplasms. We present a case of a 60-year-old woman with familial adenomatous polyposis who presented with an elevated mass in the neck of the gallbladder (measuring 16 mm × 8 mm in diameter) and multiple small cholecystic polyps. She had undergone a total colectomy for ascending colon cancer associated with familial adenomatous polyposis 22 years previously. The patient underwent laparoscopic cholecystectomy under a preoperative diagnosis of multifocal gallbladder polyps. Pathologic examination of the resected gallbladder revealed more than 70 adenomatous lesions, a feature consistent with adenoma of the gallbladder. This case suggests a requirement for long-term surveillance of the biliary system in addition to the gastrointestinal tract in patients with familial adenomatous polyposis.

Cumulative incidence and risk factors for pouch adenomas associated with familial adenomatous polyposis following restorative proctocolectomy

BACKGROUND The emergence of restorative total proctocolectomy has significantly reduced the lifetime colorectal cancer risk associated with familial adenomatous polyposis(FAP).However,adenomas may develop in the ileal pouch over time and may even progress to carcinoma.We evaluated the cumulative incidence,time to development,and risk factors associated with ileal pouch adenoma.AIM To evaluate the cumulative incidence,time to development,and risk factors associated with pouch adenoma.METHODS In this retrospective,observational study conducted at a tertiary center,95 patients with FAP who underwent restorative proctocolectomy at our center between 1989 and 2018 were consecutively included.The mean follow-up period was 88 mo.RESULTS Pouch adenomas were found in 24(25.3%)patients,with a median time of 52 mo to their first formation.Tubular adenomas were detected in most patients(95.9%).There were no high-grade dysplasia or malignancies.Of the 24 patients with pouch adenomas,13 had all detected adenomas removed.Among the 13 patients who underwent complete adenoma removal,four(38.5%)developed recurrence.Among 11(45.8%)patients with numerous polyps within the pouch,seven(63.6%)exhibited progression of pouch adenoma.The cumulative risks of pouch adenoma development at 5,10,and 15 years after pouch surgery were 15.2%,29.6%,and 44.1%,respectively.Severe colorectal polyposis(with more than 1000 polyps)was a significant risk factor for pouch adenoma development(hazard ratio,2.49;95% confidence interval:1.04-5.96;P=0.041).CONCLUSION Pouch adenomas occur at a fairly high rate in association with FAP after restorative proctocolectomy,and a high colorectal polyp count is associated with pouch adenoma development.

Three Novel Mutations of APC Gene Found in a Chinese Family with Familial Adenomatous Polyposis

Objective:To identify the causative adenomatous polyposis coli(APC)gene defects associated with a pedigree of familial adenomatous polyposis(FAP).Methods:FAP was diagnosed based on clinical manifestations,family history,as well as endoscopic and pathological examinations.The blood samples of the FAP pedigree members,colonic polyp patients,and normal individuals were collected.Genomic DNA was then extracted from those samples.APC mutation analysis was conducted via direct polymerase chain reaction(PCR)sequencing.Results:Three synonymous mutations and a missense mutation were found:c.5034G>A(p.Glyl678Gly),c.5465T>A(p.Vall 822Asp),c.5880G>A(p.Prol960Pro),and c.5274T>G(p.Serl758Ser)・Among them,the homozygous mutation on APC gene c.5034G>A has been reported,while the other three mutations have not been reported in the Chinese Han population.Individuals with c.5465T>A(p.Vall822ASP)missense mutation eventually suffer from colon cancer and have poor prognosis.We found no mutation in patients with simple intestinal polyp and in normal individuals.In addition,there were homozygous and heterozygous mutations in different patients from the same family.Conclusion:Three new mutations of APC gene were firstly reported in Han population.The missense mutation of c.5465T>A(p.Vall 822Asp)may be the cause of carcinogenesis in this FAP pedigree with poor prognosis.

Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis

Fundic gland polyps are now commonly recognized during endoscopy. These polyps are benign, often multiple and usually detected in the gastric body and fundus. In the past, these polyps were sometimes associated with familial adenomatous polyposis. In recent years, it has become evident that increasing numbers of these polyps are being detected during endoscopic studies, particularly in patients treated with proton pump inhibitors for prolonged periods. In some, dysplastic changes in these polyps have also been reported. Recent studies have suggested that there may be no increase in risk of colon cancer with long-term proton pump inhibitor therapy. While temporarily reassuring, ongoing vigilance, particularly in those genetically predisposed to colon cancer, is still warranted.

Future therapeutic implications of new molecular mechanism of colorectal cancer

High incidence(10.2%)and mortality(9.2%)rates led to the ranking of colorectal cancer(CRC)as the second most malignant tumor spectrum worldwide in 2020.Treatment strategies are becoming highly dependent on the molecular characteristics of CRC.The classical theories accept two models depicting the origin of CRC:The progression of adenoma to cancer and transformation from serrated polyps to cancer.However,the molecular mechanism of CRC development is very complex.For instance,CRCs originating from laterally spreading tumors(LST)do not adhere to any of these models and exhibit extremely serious progression and poor outcomes.In this article,we present another possible pathway involved in CRC development,particularly from LST,with important molecular characteristics,which would facilitate the design of a novel strategy for targeted therapy.

Clinical features of familial adenomas polyps in Chinese and establishment of its immortal lymphocyte cell lines

AIM： To reserve the rare Chinese familial adenomas polyp （FAP） family resource and to investigate the clinical features of FAP in Chinese for its diagnosis. METHODS： Clinical features of patients with FAP were investigated. If there is any question, their medical records were verified. Blood sample was taken and lymphocyte immortal cell lines were established with modified EB-transformation methods. Congenital hypertrophy of retinal pigment epithelium （CHRPE） was checked by an experienced ophthalmologist. RESULTS： Twenty seven families including 21 classical FAP （CFAP） families, 3 attenuated FAP （AFAP） families, and 3 suspected AFAP families were investigated. A total of 116 lymphocyte immortal cell lines were established from 26 families. In all the FAP families, colorectal cancer occurred at the mean age of 42.84 years. Of the 16 families checked, 15 （93.75%） had CHRPE. The mean number of patients suffering from colorectal neoplasm was 3.14 in CFAP families and 2.0 in AFAP families （P 〈 0.01）. The mean oldest age at diagnosis of FAP was 41.75 years in CFAP families, and 58.67 years in AFAP families, respectively （P 〈 0.01）. Mean age of development of colorectal cancer was 42.23 in CFAP and 57.33 years old in AFAP （P 〈 0.01）. Mean of the earliest age at diagnosis of FAP was 29.95 years in the FAP families with a positive family history and 46.80 years in the FAP families with a negative family history （P 〈 0.01）. The ratio of extra-intestinal tumors to colorectal neoplasms was different in the two kinds of families with positive and negative family history （P 〈 0.01）. CONCLUSION： Additional use of ciclosporin will effectively improve to establish lymphocyte immortal cell lines with modified EB- transformation methods. In Chinese FAP, there was a high frequency of CHRPE, and a later age at diagnosis and a later age of development of colorectal cancer in AFAR And earlier age at diagnosis in FAP with positive family history was also found that will help to diagnose various kinds of FAP in Chinese.