Gastrointestinal polyposis syndromes are primarily characterized by multiple polyps in the gastrointestinal tract, with their pathogenic mechanisms largely related to genetic factors and involving multiple signaling pathways. Adenomatous polyposis syndromes are mainly associated with APC gene variants, while some cases may arise from MUTYH gene variants. Peutz-Jeghers syndrome is primarily linked to STK11 gene variants. Juvenile polyposis syndrome is mainly associated with variants in the SMAD4 and BMPR1A genes. PTEN hamartoma tumor syndrome is predominantly caused by PTEN gene variants. Hereditary mixed polyposis syndrome is primarily related to variants of the GREM1 and BMPR1A genes. This article systematically summarizes the advances in genetic research on Gastrointestinal polyposis syndromes to enhance clinicians' understanding of these diseases and improve their diagnostic and therapeutic approaches.
Humans ; Adenomatous Polyposis Coli/genetics* ; Smad4 Protein/genetics* ; Peutz-Jeghers Syndrome/genetics* ; PTEN Phosphohydrolase/genetics* ; Bone Morphogenetic Protein Receptors, Type I/genetics* ; Intestinal Polyposis/congenital* ; Intercellular Signaling Peptides and Proteins/genetics* ; Adenomatous Polyposis Coli Protein/genetics* ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinase Kinases ; Neoplastic Syndromes, Hereditary

OBJECTIVE: To analyze the clinical features and genetic basis for a Chinese pedigree affected with familial adenomatous polyposis (FAP). METHODS: Clinical information of the patient was collected. Genomic DNA was extracted from peripheral blood sample of the patient and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 33-year-old female, was found to have multiple adenomatous polyps in the intestine. WES revealed that she has harbored a heterozygous variant of the APC gene, namely c.1922dupA (p.N641fs*10), which was unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic. CONCLUSION The c.1922dupA (p.N641fs*10) variant of the APC gene probably underlay the FAP in this pedigree. Above finding has enabled genetic counseling for this family.
Female ; Humans ; Adult ; Pedigree ; Adenomatous Polyposis Coli Protein/genetics* ; Germ-Line Mutation ; Adenomatous Polyposis Coli/genetics* ; China ; Mutation

OBJECTIVE: To explore the genetic basis for a pedigree affected with familial adenomatous polyposis (FAP). METHODS: The proband, with recurrence of blood in the stool, was diagnosed with FAP by endoscopy, pathological examination and a family history. She was subjected to next generation sequencing to detect genetic variant. Suspected variant was verified by Sanger sequencing of members from her pedigree. RESULTS: The proband, her mother and brother were found to carry a heterozygous c.532-1G>A variant of the APC gene, which may lead to aberrant splicing of mRNA resulting in a truncated protein, which may lose its normal function and promote the tumorigenesis. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.532-1G>A variant of APC gene was predicted to be pathogenic(PVS1+PP1+PP4+PP5). CONCLUSION The c.532-1G>A variant of the APC gene probably underlay the pathogenesis of FAP in this pedigree.
Adenomatous Polyposis Coli/genetics* ; Adenomatous Polyposis Coli Protein/genetics* ; Female ; Genes, APC ; Humans ; Male ; Neoplasm Recurrence, Local ; Pedigree

Familial adenomatous polyposis (FAP) is one of the most common hereditary colorectal cancers. Its intestinal and extra-intestinal manifestations are correlated with mutation sties of the APC gene. Potential gene modulation sites in patients who have typical clinical manifestations but with unidentified APC mutations are also discussed, which included MUTYH gene, AXIN gene and certain epigenetic changes. With the generalization of Precision Medicine, to offer individualized treatment and surveillance strategy based on the genotype-phenotype correlation will be of great value for FAP patients. This review focuses on the research advance in genotype - phenotype correlation studies of FAP patients.
Adenomatous Polyposis Coli ; genetics ; Axin Protein ; genetics ; DNA Glycosylases ; genetics ; Genes, APC ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Mutation ; beta Catenin ; genetics

OBJECTIVETo analyze the characteristics of germline mutations of adenomatous polyposis coli (APC) gene in pedigrees affected with familial adenomatous polyposis (FAP).

METHODSGenomic DNA was extracted from peripheral blood samples from members of the 13 FAP pedigrees. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large fragment deletions of the APC gene. Subsequently, potential mutation was screened from all exons of the APC gene with PCR amplification and direct sequencing.

RESULTSGermline mutations have been identified in 5 FAP pedigrees, which included c.3184_3187delCAAA, c.5432C>T, c.3925_3928delAAAA and c.3925_3929del AAAAG(in two pedigrees). Small deletional mutations were found primarily in the area of AAAAG tandem repeat sequences.

CONCLUSIONC.3925_3929 located in AAAAG tandem repeats is probably the hot spot for APC gene mutations, which are mostly deletional mutations, especially the 5 bp base deletion at codon 1309.

Adenomatous Polyposis Coli ; genetics ; Adenomatous Polyposis Coli Protein ; genetics ; Adult ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; China ; Female ; Humans ; Male ; Molecular Sequence Data ; Pedigree ; Sequence Deletion

OBJECTIVETo analyze mutation of adenomatous polyposis coli (APC) gene in a family affected with familial adenomatous polyposis.

METHODSThe diagnosis was made based on clinical manifestations, family history, presence of numerous polyps in the colon as well as pathological examination. Peripheral blood samples were collected, and genomic DNA was extracted. Potential mutation of the APC gene was detected by polymerase chain reaction (PCR) and DNA sequencing. After finding the mutation in the proband, the same mutation was screened among other family members. The mutation was also confirmed with PCR-restriction fragment length polymorphism (RFLP), with which 100 unrelated healthy controls were examined.

RESULTSA novel heterozygous nonsense mutation c.2891T>G (L964X) of the APC gene was identified in this pedigree. The mutation has led to premature termination of translation. The same mutation was not detected among the 100 healthy controls.

CONCLUSIONThe c.2891T>G (L964X) of the APC gene probably underlies the familial adenomatous polyposis in this pedigree. The combined DNA sequencing and PCR-RFLP method is efficient and accurate for the diagnosis.

Adenomatous Polyposis Coli ; diagnosis ; genetics ; Adenomatous Polyposis Coli Protein ; genetics ; Adult ; Base Sequence ; Child, Preschool ; Colorectal Neoplasms ; diagnosis ; genetics ; Female ; Humans ; Male ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Point Mutation ; Young Adult

OBJECTIVETo study the expression of Wnt5a gene mRNA and Wnt5a, APC, β-catenin proteins in human colorectal adenocarcinoma (CRC) and explore its clinical significance.

METHODSWnt5a mRNA level was measured in 30 patients with CRC and paired non-tumor tissues by real-time PCR. Immunohistochemical staining of Wnt5a, APC, β-catenin was performed in samples of 62 patients with CRC using SP system.

RESULTSThe relative expression level of Wnt5a mRNA in fresh CRC is 0.1232 ± 0.0140, which is significantly higher than that in adjacent colorectal mucosa (0.0497 ± 0.0074, P = 0.02). A low expression of Wnt5a protein was observed in 38 of 62 CRC. Wnt5a protein expression was closely correlated with the tumor types and the degree of tumor differentiation (P < 0.05). There was no apparent relationship with lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). APC protein was decreased in 38 of 62 CRC. The expression of APC was closely correlated with the tumor types (P < 0.05). There was no apparent relationship with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). The expression of β-catenin was observed in cytoplasm and/or cell nuclei in 50 of 62 CRC. The positive rate of β-catenin expression was closely correlated with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P < 0.05). There was no apparent relationship with the tumor types (P > 0.05). The expressions of Wnt5a (r = 0.271, P = 0.027) and APC (r = 0.343, P = 0.004) were correlated with that of β-catenin in CRC, respectively, but there was no correlation between the expressions of Wnt5a and APC protein (r = 0.218, P = 0.078) in the tumors.

CONCLUSIONSWnt5a, APC and β-catenin genes might be involved in the carcinogenesis and development of CRC. It is hypothesized that down-regulation of APC and Wnt5a proteins may be one of causes of ectopic expression of β-catenin in CRC.

Adenocarcinoma ; metabolism ; pathology ; Adenocarcinoma, Mucinous ; metabolism ; pathology ; Adenomatous Polyposis Coli Protein ; metabolism ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Signet Ring Cell ; metabolism ; pathology ; Cell Differentiation ; Colorectal Neoplasms ; metabolism ; pathology ; Down-Regulation ; Female ; Genes, APC ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; Proto-Oncogene Proteins ; genetics ; metabolism ; RNA, Messenger ; metabolism ; Real-Time Polymerase Chain Reaction ; Wnt Proteins ; genetics ; metabolism ; Wnt-5a Protein ; beta Catenin ; metabolism

OBJECTIVETo screen out specifically-expressed serum protein markers in familial adenomatous polyposis (FAP) and to establish a serum protein fingerprint diagnostic model for distinguishing FAP from sporadic colorectal adenomas.

METHODSSerum samples were collected from 19 FAP cases and 16 sporadic colorectal adenomas with informed consent. Serum protein fingerprint profiles were detected by SELDI-TOF-MS with CM 10 protein chip to screen out FAP adenoma-related serum protein markers, and support vector machine (SVG) technique was used to establish the diagnostic model to distinguish FAP from sporadic colorectal adenomas.

RESULTSSix differently-expressed protein peaks (P < 0.01) were detected. Among them proteins of 5640, 3160, 4180 and 4290 m/z were highly expressed in FAP adenomas, and proteins of 3940 and 3400 m/z were highly expressed in sporadic colorectal adenomas. The accuracy of diagnostic model established with SVG to distinguish FAP adenomas and sporadic colorectal adenomas was 94.7% and 93.7%, respectively.

CONCLUSIONSELDI-TOF-MS can be effectively used to screen out the differentially expressed serum protein markers in FAP adenomas and sporadic colorectal adenomas, and a diagnostic model build by SVG to distinguish them has been successfully established. Therefore, a useful breakthrough point for research on molecular mechanisms of FAP pathogenesis is provided.

Adenoma ; genetics ; metabolism ; Adenomatous Polyposis Coli ; genetics ; metabolism ; Adult ; Aged ; Biomarkers, Tumor ; metabolism ; Colorectal Neoplasms ; genetics ; metabolism ; Diagnosis, Differential ; Female ; Gene Expression Profiling ; Humans ; Male ; Middle Aged ; Protein Array Analysis ; Proteomics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

OBJECTIVETo investigate the correlation of hypermethylation of BRCA1 and APC gene promoters with the response to anthracycline-based neoadjuvant chemotherapy in primary breast cancer.

METHODSOne hundred and forty patients with primary breast cancer received anthracycline-based neoadjuvant chemotherapy, and pretreatment hypermethylation status of BRCA1 and APC genes promoters was detected by methylation-specific PCR.

RESULTSOf the 140 patients, 30 (21.4%) achieved pathological complete response (pCR), and methylation rates of BRCA1 and APC gene promoters were 21.4% (30/140) and 18.3% (24/131), respectively. Among the 110 patients with unmethylated BRCA1 gene, 28 (25.5%) achieved pCR, while in the 30 patients with methylated BRCA1 gene, only 2 (6.7%) had a pCR, with a significant difference between the two groups (chi(2) = 4.94, P = 0.026). However, no statistically significant correlation was found between the methylation of APC gene and pCR to neoadjuvant chemotherapy in this cohort of patients (P > 0.05).

CONCLUSIONPrimary breast cancer with an unmethylated BRCA1 gene is prone to achieve a pathological complete response to anthracycline-based neoadjuvant chemotherapy than those with a methylated BRCA1 gene. BRCA1 methylation status may be a useful predictor for anthracycline-based neoadjuvant chemotherapy in primary breast cancer patients.

Adenomatous Polyposis Coli Protein ; genetics ; metabolism ; Adult ; Aged ; Anthracyclines ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; BRCA1 Protein ; genetics ; metabolism ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; CpG Islands ; genetics ; Cyclophosphamide ; therapeutic use ; DNA Methylation ; Epirubicin ; therapeutic use ; Female ; Fluorouracil ; therapeutic use ; Humans ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Staging ; Remission Induction ; Young Adult

OBJECTIVETo explore the role of abnormalities of chromosome 8, APC and beta-catenin genes in tumorigenesis of aggressive fibromatosis.

METHODSTrisomy 8 was detected by interphase fluorescence in situ hybridization (FISH). The APC gene and beta-catenin gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) and direct sequence analysis after the PCR transition.

RESULTSThe rate of trisomy 8 in recurrent tumors (62.5%, 5/8) was significantly higher than that in the primary tumors (8.3%, 1/12). Somatic substitution of APC gene was found in 18 of 69 (26.1%) aggressive fibrometases. Somatic transition of beta-catenin gene was detected in 13 of 69 (18.8%) and mutation at codon 41 in exon 3 involving threonine residues implicated in the degradation of beta-catenin. The abnormal expression of beta-catenin had no significant correlation with the mutation of APC or beta-catenin gene. The group with positively expressed beta-catenin protein showed a significant higher c-myc protein expression than those without (P = 0.001). The Ki-67 index was extremely low in all the lesions. The apoptosis index (AI) of the groups with positively expressed c-myc and cyclin D1 showed significantly lower AI than those without.

CONCLUSIONTrisomy 8 may serve as a useful predictor of recurrence in aggressive fibromatosis. There are somatic mutations of the APC and beta-catenin genes in the aggressive fibromatosis, and there are abnormalities in the Wnt signaling pathway. These abnormalities may result in the aberrances of cell proliferation and apoptosis, which are likely to be import factors in the tumorigenesis.

Adenomatous Polyposis Coli Protein ; genetics ; metabolism ; Apoptosis ; Chromosomes, Human, Pair 8 ; Cyclin D1 ; metabolism ; Fibromatosis, Aggressive ; genetics ; metabolism ; pathology ; Genes, APC ; Humans ; Ki-67 Antigen ; metabolism ; Neoplasm Recurrence, Local ; Point Mutation ; Proto-Oncogene Proteins c-myc ; metabolism ; Signal Transduction ; Trisomy ; Wnt Proteins ; metabolism ; beta Catenin ; genetics ; metabolism