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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 -
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 -
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 -
Journal of Gastroenterology Apr 2021The Japanese Society of Gastroenterology (JSGE) published ''Daicho Polyp Shinryo Guideline 2014'' in Japanese and a part of this guideline was published in English as... (Review)
Review
BACKGROUND
The Japanese Society of Gastroenterology (JSGE) published ''Daicho Polyp Shinryo Guideline 2014'' in Japanese and a part of this guideline was published in English as "Evidence-based clinical practice guidelines for management of colorectal polyps" in the Journal of Gastroenterology in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version.
METHODS
The guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references.
RESULTS
The professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas).
CONCLUSIONS
After evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.
Topics: Colonic Polyps; Disease Management; Evidence-Based Practice; Guidelines as Topic; Humans; Japan
PubMed: 33710392
DOI: 10.1007/s00535-021-01776-1 -
American Journal of Human Genetics May 2022We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER)...
We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Endodeoxyribonucleases; Genetic Predisposition to Disease; Germ Cells; Germ-Line Mutation; Humans; Uveal Neoplasms
PubMed: 35460607
DOI: 10.1016/j.ajhg.2022.03.018 -
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 -
Genetics in Medicine : Official Journal... Dec 2020Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors,...
PURPOSE
Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study.
METHODS
POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation.
RESULTS
Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome.
CONCLUSIONS
Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
Topics: Colorectal Neoplasms; DNA Polymerase II; DNA Polymerase III; Germ-Line Mutation; Humans; Mutation; Poly-ADP-Ribose Binding Proteins
PubMed: 32792570
DOI: 10.1038/s41436-020-0922-2 -
International Journal of Molecular... Dec 2020Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able... (Review)
Review
Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients.
Topics: Adenomatous Polyposis Coli Protein; Animals; Cell Movement; Chromosomal Instability; Chromosomes, Human, Pair 18; Colon; Colorectal Neoplasms; CpG Islands; Disease Progression; ErbB Receptors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Loss of Heterozygosity; Microsatellite Repeats; Neoplasm Metastasis; Phenotype; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Risk; Signal Transduction; Tumor Suppressor Protein p53; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 33374459
DOI: 10.3390/ijms22010130 -
Cell Reports Jan 2020Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how...
Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in Apc mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer.
Topics: Adaptor Proteins, Signal Transducing; Adenomatous Polyposis Coli; Animals; Azoxymethane; Carcinogenesis; Cell Adhesion Molecules; Cell Proliferation; Colitis; Colorectal Neoplasms; Dextran Sulfate; Focal Adhesion Protein-Tyrosine Kinases; Humans; Inflammation; Integrins; Interleukin-6; Intestines; Mice, Inbred C57BL; Myofibroblasts; Precancerous Conditions; STAT3 Transcription Factor; Signal Transduction; Stromal Cells; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins; src-Family Kinases
PubMed: 31968254
DOI: 10.1016/j.celrep.2019.12.075