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Best Practice & Research. Clinical... 2022Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare inherited polyposis syndromes with a high colorectal cancer (CRC) risk. Therefore,... (Review)
Review
Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare inherited polyposis syndromes with a high colorectal cancer (CRC) risk. Therefore, frequent endoscopic surveillance including polypectomy of relevant premalignant lesions from a young age is warranted in patients. In FAP and less often in MAP, prophylactic colectomy is indicated followed by lifelong endoscopic surveillance of the retained rectum after (sub)total colectomy and ileal pouch after proctocolectomy to prevent CRC. No consensus is reached on the right type and timing of colectomy. As patients with FAP and MAP nowadays have an almost normal life-expectancy due to adequate treatment of colorectal polyposis, challenges in the management of FAP and MAP have shifted towards the treatment of duodenal and gastric adenomas as well as desmoid treatment in FAP. Whereas up until recently upper gastrointestinal surveillance was mostly diagnostic and patients were referred for surgery once duodenal or gastric polyposis was advanced, nowadays endoscopic treatment of premalignant lesions is widely performed. Aiming to reduce polyp burden in the colorectum as well as in the upper gastrointestinal tract, several chemopreventive agents are currently being studied.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Colorectal Neoplasms; Humans; Stomach Neoplasms
PubMed: 35988966
DOI: 10.1016/j.bpg.2022.101793 -
Archives of Pathology & Laboratory... Nov 2019Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to... (Review)
Review
CONTEXT.—
Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP.
OBJECTIVE.—
To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification.
DATA SOURCES.—
This review will be based on peer-reviewed literature and the authors' experiences.
CONCLUSIONS.—
In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Brain Neoplasms; Colorectal Neoplasms; Gardner Syndrome; Humans; Immunohistochemistry; Mutation; Neoplastic Syndromes, Hereditary; Prognosis; Skin
PubMed: 31070935
DOI: 10.5858/arpa.2018-0570-RA -
Molecular Aspects of Medicine Oct 2019The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new... (Review)
Review
The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.
Topics: Adenomatous Polyposis Coli; Alleles; Biomarkers; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Predisposition to Disease; Genetic Variation; Germ-Line Mutation; Humans
PubMed: 30862463
DOI: 10.1016/j.mam.2019.03.001 -
BJS Open May 2023Inheritance patterns show familial clustering of gastrointestinal cancers, and multiple germline conditions have now been identified that predispose to colorectal,... (Review)
Review
BACKGROUND
Inheritance patterns show familial clustering of gastrointestinal cancers, and multiple germline conditions have now been identified that predispose to colorectal, gastric, and pancreatic cancers.
METHODS
A narrative review based on recent relevant literature was conducted.
RESULTS
Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer, increases the risk of several abdominal cancers, with the highest population prevalence. Familial adenomatous polyposis and some of the more infrequent polyposis syndromes have distinct characteristics affecting various organ-specific cancer risks. Hereditary gastric and pancreatic cancer syndromes include those also causing colorectal cancer, while additional genetic disorders predisposing only to upper gastrointestinal malignancies have been recognized more recently. Diagnosing and managing hereditary cancer syndromes requires multidisciplinary expertise and may be best managed in tertiary centres, with a need to consider patient preference and ensure shared decision-making.
CONCLUSION
Several germline conditions predispose to colorectal, gastric, and pancreatic cancer, which inform identification, surveillance regimens, prevention, cascade screening, counselling, and surgical management. The authors describe developments in the hereditary origin of colorectal, gastric, and pancreatic cancer with current recommendations in surveillance and surgical management.
Topics: Humans; Adenomatous Polyposis Coli; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms; Gastrointestinal Neoplasms; Pancreatic Neoplasms
PubMed: 37165697
DOI: 10.1093/bjsopen/zrad023 -
International Journal of Molecular... Jan 2023Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and... (Review)
Review
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome ( gene), -associated polyposis ( gene), Peutz-Jeghers syndrome ( gene), Cowden syndrome ( gene), and juvenile polyposis syndrome ( and genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as , , , , , , and . In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
Topics: Humans; Genetic Predisposition to Disease; Adenomatous Polyposis Coli; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Testing; Colorectal Neoplasms
PubMed: 36768460
DOI: 10.3390/ijms24032137 -
Cells Sep 2020The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated... (Review)
Review
The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.
Topics: Adenomatous Polyposis Coli Protein; Carcinogenesis; Chromatin; Colorectal Neoplasms; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Proteasome Endopeptidase Complex; Proteolysis; Signal Transduction; TCF Transcription Factors; Transcription, Genetic; Wnt Proteins; beta Catenin
PubMed: 32961708
DOI: 10.3390/cells9092125 -
Cancer Aug 2022Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease... (Review)
Review
Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracycline-based or methotrexate-based regimens). A newer class of agents, γ-secretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients.
Topics: Adenomatous Polyposis Coli; Fibromatosis, Aggressive; Humans; Prognosis; Soft Tissue Neoplasms; beta Catenin
PubMed: 35670122
DOI: 10.1002/cncr.34332 -
Endoscopy Sep 2019ESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and...
ESGE recommends that individuals with hereditary gastrointestinal polyposis syndromes should be surveilled in dedicated units that provide monitoring of compliance and endoscopic performance measures. Strong recommendation, moderate quality of evidence, level of agreement 90 %.ESGE recommends performing esophagogastroduodenoscopy, small-bowel examination, and/or colonoscopy earlier than the planned surveillance procedure if a patient is symptomatic. Strong recommendation, low quality of evidence, level of agreement 100 %.
Topics: Adenomatous Polyposis Coli; Colectomy; Early Detection of Cancer; Endoscopy, Gastrointestinal; Humans; Population Surveillance
PubMed: 31342472
DOI: 10.1055/a-0965-0605 -
Gut Jul 2020Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum...
OBJECTIVE
Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of adenomas at different evolutionary stages in the colon and rectum that will inevitably progress to adenocarcinomas if left untreated. Here, we investigated the genetic alterations and transcriptomic transitions from precancerous adenoma to carcinoma.
DESIGN
Whole-exome sequencing, whole-genome sequencing and single-cell RNA sequencing were performed on matched adjacent normal tissues, multiregionally sampled adenomas at different stages and carcinomas from six patients with FAP and one patient with -associated polyposis (n=56 exomes, n=56 genomes and n=8,757 single cells). Genomic alterations (including copy number alterations and somatic mutations), clonal architectures and transcriptome dynamics during adenocarcinoma carcinogenesis were comprehensively investigated.
RESULTS
Genomic evolutionary analysis showed that adjacent lesions from the same patient with FAP can originate from the same cancer-primed cell. In addition, the tricarboxylic acid cycle pathway was strongly repressed in adenomas and was then slightly alleviated in carcinomas. Cells from the 'normal' colon epithelium of patients with FAP already showed metabolic reprogramming compared with cells from the normal colon epithelium of patients with sporadic colorectal cancer.
CONCLUSIONS
The process described in the previously reported field cancerisation model also occurs in patients with FAP and can contribute to the formation of adjacent lesions in patients with FAP. Reprogramming of carbohydrate metabolism has already occurred at the precancerous adenoma stage. Our study provides an accurate picture of the genomic and transcriptomic landscapes during the initiation and progression of carcinogenesis, especially during the transition from adenoma to carcinoma.
Topics: Adenomatous Polyposis Coli; Carcinogenesis; Female; Gene Expression Profiling; Humans; Male; Metabolic Networks and Pathways; Pedigree; Precancerous Conditions; Sequence Analysis, RNA; Single-Cell Analysis; Exome Sequencing; Whole Genome Sequencing
PubMed: 31744909
DOI: 10.1136/gutjnl-2019-319438