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Genes Mar 2023Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer,... (Review)
Review
Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.
Topics: Humans; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms, Hereditary Nonpolyposis; Germ-Line Mutation; Thyroid Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 36980956
DOI: 10.3390/genes14030684 -
American Society of Clinical Oncology... 2014Lynch syndrome was described over a century ago but information on the medical consequences and optimal management of this disorder continue to amass and evolve. This... (Review)
Review
Lynch syndrome was described over a century ago but information on the medical consequences and optimal management of this disorder continue to amass and evolve. This brief overview highlights the gene-specific and site-specific cancer penetrance and management options for those with Lynch syndrome.
Topics: Animals; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Predisposition to Disease; Heredity; History, 20th Century; History, 21st Century; Humans; Molecular Diagnostic Techniques; Pedigree; Phenotype; Predictive Value of Tests; Prevalence; Risk Factors; Treatment Outcome
PubMed: 24857057
DOI: 10.14694/EdBook_AM.2014.34.27 -
The Surgical Clinics of North America Oct 2015Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC... (Review)
Review
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis.
Topics: Adenomatous Polyposis Coli; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; Early Detection of Cancer; Genetic Predisposition to Disease; Humans
PubMed: 26315524
DOI: 10.1016/j.suc.2015.05.004 -
Cancer Biology & Medicine Jun 2022Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening...
OBJECTIVE
Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs.
METHODS
Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis.
RESULTS
The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of , , and , as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction.
CONCLUSIONS
MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.
Topics: Humans; China; Colorectal Neoplasms, Hereditary Nonpolyposis; Early Detection of Cancer; Microsatellite Instability; Proto-Oncogene Proteins p21(ras); TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A
PubMed: 35638907
DOI: 10.20892/j.issn.2095-3941.2021.0585 -
World Journal of Gastroenterology Jun 2015Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other... (Review)
Review
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers due to inherited mutations in mismatch repair (MMR) genes. During the last decades, there have been great advances in research on Chinese Lynch syndrome. This review mainly focuses on the genetic basis, clinicopathologic features, diagnosis, intervention, chemoprevention, and surveillance of Lynch syndrome in China. In addition to frequently altered MMR genes, such as MLH1, MSH2, MSH6, and MLH3, other MMR-associated genes, such as those encoding human exonuclease 1, transforming growth factor β receptor 2, and alanine aminopeptidase, metastasis-associated protein 2, adenomatosis polyposis coli down-regulated 1, and hepatic and glial cell adhesion molecule have also been implicated in Chinese Lynch syndrome. Most Chinese researchers focused on the clinicopathologic features of Lynch syndrome, and it is noticeable that the most frequent extracolonic tumor in northeast China is lung cancer, which is different from other areas in China. The Chinese diagnostic criteria for Lynch syndrome have been established to identify gene mutation or methylation. With regard to chemoprevention, celecoxib may be effective to prevent polyps relapse in Lynch syndrome carriers. Additionally, a colonoscopy-based surveillance strategy for the prevention and early detection of neoplasms in Lynch-syndrome carriers has been proposed.
Topics: Animals; Anticarcinogenic Agents; Asian People; Celecoxib; China; Colonoscopy; Colorectal Neoplasms, Hereditary Nonpolyposis; Early Detection of Cancer; Genetic Markers; Genetic Predisposition to Disease; Humans; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 26078562
DOI: 10.3748/wjg.v21.i22.6861 -
Familial Cancer Jan 2022
Review
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Humans; Risk; Stomach Neoplasms
PubMed: 33611683
DOI: 10.1007/s10689-021-00235-3 -
Cancer Prevention Research... Dec 2020Lynch syndrome is a prevalent hereditary cancer predisposition syndrome. While colorectal cancer is the most common gastrointestinal (GI) cancer in Lynch syndrome, there...
Lynch syndrome is a prevalent hereditary cancer predisposition syndrome. While colorectal cancer is the most common gastrointestinal (GI) cancer in Lynch syndrome, there is also increased risk of gastric and small intestinal cancers. Recommendations for upper GI cancer surveillance in Lynch syndrome vary widely with limited data supporting effectiveness. Herein, we collected data on individuals with a diagnosis of Lynch syndrome seen at our tertiary care referral center. We identified individuals who underwent upper endoscopy and those with upper GI cancers, and associated demographics, genetic testing results, and endoscopic information. Standard statistical analyses were performed. Among 295 individuals with Lynch syndrome seen at our center, 217 (73.6%) underwent 660 total upper endoscopies. Of these 217, precancerous upper endoscopy findings included Barrett's esophagus (7, 3.2%), gastric intestinal metaplasia (18, 8.3%), and duodenal adenomas (4, 1.8%), and was identified in 6 (2.8%). Upper GI cancers were diagnosed in 11 individuals (3.7%), including esophageal in 1, gastric in 6, and duodenal in 4. Five (1.7%) of these upper GI cancers were identified on surveillance. Individuals with upper GI cancers identified on surveillance were older at first surveillance endoscopy, with median age 63.3 versus 44.9 years ( < 0.001). Of the upper GI cancers detected on surveillance, 80% (4/5) occurred within 2 years of last upper endoscopy and 80% were stage I. In conclusion, upper endoscopy surveillance in Lynch syndrome identifies upper GI cancers. For individuals with Lynch syndrome who undergo upper GI surveillance, a short surveillance interval may be warranted.
Topics: Adenocarcinoma; Adult; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; Duodenal Neoplasms; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastroscopy; Humans; Male; Middle Aged; Pennsylvania; Population Surveillance; Prognosis; Retrospective Studies; Stomach Neoplasms
PubMed: 32859614
DOI: 10.1158/1940-6207.CAPR-20-0269 -
Pathologie (Heidelberg, Germany) Nov 2023Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for... (Review)
Review
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Multicenter Studies as Topic
PubMed: 37874379
DOI: 10.1007/s00292-023-01208-2 -
Journal of Cancer Research and... Jul 2021The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated...
OBJECTIVES
The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated colorectal cancer (CRC), including Lynch-like syndrome (LLS), constitutional mismatch repair-deficiency, familial CRC type X (FCCTX), and polymerase proofreading-associated polyposis syndrome.
MATERIALS AND METHODS
1294 cases of CRC samples were detected mismatch repair (MMR) status using immunohistochemistry (IHC) staining, in which the cases with MLH1-deficient CRC underwent BRAF mutation analysis by IHC. Following the personal and/or family history survey, next-generation sequencing (NGS) was used to detect gene variants.
RESULTS
1294 CRC patients were dichotomized into tumors caused by a deficient MMR (dMMR) system and a proficient MMR (pMMR) system after MMR status analysis. 45 patients with suspected sporadic dMMR CRC were then separated from MLH1-deficient CRC though BRAF mutation status analysis by IHC. Following the personal and/or family history survey for 1294 patients, as well as germline genetic testing by NGS, 34 patients were diagnosed as LS (8 cases), SLS (13 cases), LLS ( 6 cases), FCCTX (3 cases), and sporadic CRC (4 cases).
CONCLUSIONS
Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.
Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Diagnosis, Differential; Female; Genetic Testing; Germ-Line Mutation; Humans; Immunohistochemistry; Male; Medical History Taking; Microsatellite Instability; Middle Aged
PubMed: 34269315
DOI: 10.4103/jcrt.jcrt_214_21 -
Oncotarget Mar 2017Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple...
Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.
Topics: Adenocarcinoma; Adult; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Mutational Analysis; DNA-Binding Proteins; Female; High-Throughput Nucleotide Sequencing; Humans; Incidence; Male; Microdissection; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Polymerase Chain Reaction
PubMed: 28206961
DOI: 10.18632/oncotarget.15277