Microsatellite instability,MMR gene expression and proliferation kinetics in colorectal cancer with famillial predisposition

INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated sequences,has been found.Microsatellitcs are relatively short runs of tandemlyrepeated sequences scattered throughout

Genetic predisposition to Helicobacter pylori-induced gastric precancerous conditions

Gastric cancer is the most common malignancy of the gastrointestinal tract in East Asian populations and the second most frequent cause of cancer-related mortality in the world. While previous studies have investigated the genetic factors involved in gastric carcinogenesis, there still exist relatively few studies that have investigated the genetic traits associated with the risk of gastric precancerous conditions. In this paper we will review the biology and genetic polymorphisms involved in the genesis of gastric precancerous conditions reported to date and discuss the future prospects of this field of study. The associations of gastric precancerous conditions with polymorphisms in the cytotoxin-associated gene A-related genes (e.g. PTPN11 G/A at intron 3, rs2301756), those in the genes involved in host immunity against Helico-bacter pylori (H. pylori) infection (e.g.TLR4 +3725G/C, rs11536889) or polymorphisms of the genes essential for the development/ differentiation of the gastric epithelial cells (e.g. RUNX3 T/A polymorphism at intron 3, rs760805) have been reported to date. Genetic epide-miological studies of the associations between H. pylori-induced gastric precancerous conditions and other gene polymorphisms in these pathways as well as polymor-phisms of the genes involved in other pathways like oxidative DNA damage repair pathways would provide useful evidence for the individualized prevention of these H. pylori-induced gastric precancerous conditions.

New genes emerging for colorectal cancer predisposition

Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families

Objective:Approximately 5%–10%of breast cancer(BC)patients display familial traits that are genetically inherited among the members of a family.The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.Methods:Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.Results:Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8%(96/116)of the cases.Among these,80.8%of the mutated genes were related to DNA damage repair.Fourteen possible disease-causing variants were identified in 13 of 27 BC families.Only 25.9%(7/27)of the BC families exhibited hereditary deficiency in BRCA1/2 genes,while 22.2%of the BC families exhibited defects in non-BRCA genes.In all,41.7%(40/96)of the mutation carriers had BRCA mutations,88.5%(85/96)had non-BRCA mutations,and 30.2%(29/96)had both BRCA and non-BRCA mutations.The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations(P<0.05).However,the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations(P<0.05).Conclusions:In addition to BRCA1/2,genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC.Therefore,profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Anthropometric parameter-based assessment for cardiovascular disease predisposition among young Indians

AIM:To assess the predisposition for cardiovascular diseases among young Asian Indians by anthropometric data analysis.METHODS:One hundred and thirty males and 329 females aged between 15 and 26 years,attending health care check-ups at VIT University,were included in this study.Their body mass index,systolic and diastolic blood pressure,waist circumference,waist-to-hip ratio,pulse rate and pressure,along with mean arterial pressure,were measured and the data analyzed as per World Health Organization guidelines.RESULTS:Based on the analysis,54% of the male population was found to be predisposed to cardiovascular disease.Of these,approximately 40% were at highest possible risk,with greater than threshold values of body mass index,waist circumference and waist-to-hip ratio.Females were found to have lower risk.Both genders showed significant correlation(P < 0.0001) between body mass index and waist circumference.Waist-to-hip ratio correlated significantly only in males with the former index whereas it correlated significantly with waist circumference in both genders.Receiver operating curve analysis,when performed,showed optimal sensitivity and specificity for body mass index and waist circumference.CONCLUSION:The above results indicate that seeds of cardiovascular disease may have been sown at a young age in Asian Indian populations.Interventional measures are advised to prevent accelerated atherosclerosis leading to premature cardiovascular disease.

Exosomal glypican-1 is elevated in pancreatic cancer precursors and can signal genetic predisposition in the absence of endoscopic ultrasound abnormalities

BACKGROUND Individuals within specific risk groups for pancreatic ductal adenocarcinoma(PDAC)[mucinous cystic lesions(MCLs),hereditary risk(HR),and new-late onset diabetes mellitus(NLOD)]represent an opportunity for early cancer detection.Endoscopic ultrasound(EUS)is a premium image modality for PDAC screening and precursor lesion characterization.While no specific biomarker is currently clinically available for this purpose,glypican-1(GPC1)is overexpressed in the circulating exosomes(crExos)of patients with PDAC compared with healthy subjects or those harboring benign pancreatic diseases.AIM To evaluate the capacity of GPC1+crExos to identify individuals at higher risk within these specific groups,all characterized by EUS.METHODS This cross-sectional study with a prospective unicentric cohort included 88 subjects:40 patients with MCL,20 individuals with HR,and 20 patients with NLOD.A control group(CG)was submitted to EUS for other reasons than pancreatic pathology,with normal pancreas and absence of hereditary risk factors(n=8).The inclusion period was between October 2016 and January 2019,and the study was approved by the Ethics Committee of Centro Hospitalar Universitário de São João,Porto,Portugal.All patients provided written informed consent.EUS and blood tests for quantification of GPC1+crExos by flow cytometry and carbohydrate antigen 19-9(CA 19-9)levels by ELISA were performed in all subjects.EUS-guided tissue acquisition was done whenever necessary.For statistical analysis,SPSS®27.0(IBM Corp.,Armonk,NY,United States)version was used.All graphs were created using GraphPad Prism 7.00(GraphPad Software,San Diego,CA,United States).RESULTS Half of MCLs harbored worrisome features(WF)or high-risk stigmata(HRS).Pancreatic abnormalities were detected by EUS in 10.0%and 35.0%in HR and NLOD individuals,respectively,all considered non-malignant and“harmless.”Median levels of GPC1+crExos were statistically different:MCL[99.4%,interquartile range(IQR):94.9%-99.8%],HR(82.0%,IQR:28.9%-98.2%),NLOD(12.6%,IQR:5.2%-63.4%),and CG(16.2%,IQR:6.6%-20.1%)(P<0.0001).Median levels of CA 19-9 were within the normal range in all groups(standard clinical cut-off of 37 U/mL).Within HR,individuals with a positive history of cancer had higher median levels of GPC1+crExos(97.9%;IQR:61.7%-99.5%),compared to those without(59.7%;IQR:26.3%-96.4%),despite no statistical significance(P=0.21).Pancreatic cysts with WF/HRS were statistically associated with higher median levels of GPC1+crExos(99.6%;IQR:97.6%-99.8%)compared to those without(96.5%;IQR:81.3%-99.5%)(P=0.011),presenting an area under the receiver operating characteristic curve value of 0.723(sensitivity 75.0%and specificity 67.7%,using a cutoff of 98.5%;P=0.012).CONCLUSION GPC1+crExos may act as biomarker to support the diagnosis and stratification of PDAC precursor lesions,and in signaling individuals with genetic predisposition in the absence of EUS abnormalities.

Genetic Predisposition to Retinoblastoma (Rb)

Determination of 8 cytogenetic indicators in 14 cases of Rb,their 21 parents and 14 normal controls revealed various degrees ofchromosome instability and nondisjunction in the patients and their parents,indicating the presence of genetic neoplastic predisposition to neoplasm inRb patients.Eye Science 1993;9:149-152.

Development of Feet Edema on Contact with a Cemented Floor in Specific Individuals with Genetic Predisposition

Edema is a sign/symptom which has origin diverse causes and mechanisms of installations. I do believe that it can be classified into appendicular and axial edemas with reference to the body division rather than the present classification of peripheral edema and other edemas. Edema being a sign/symptom as an entity does cause other signs and symptoms in the body. From observations, I do believe that a cemented floor causes the development of feet edema in specific individuals with genetic predisposition. This can be confirmed by the fact that when these persons place their feet on somewhere else rather than the floor, they do not develop an edema.

Genetic predisposition to childhood cancer

The etiology of childhood cancer remains largely unknown.Recent evidence suggests that genetic factors play a substantial role in pediatric tumorigenesis.Unlike adult cancers,pediatric cancers typically have a higher prevalence of germline pathogenic variants in cancer predisposition genes.Inherited cancer predisposition syndromes account for approximately 10%of all childhood cancers.Over the years,the diagnosis of cancer predisposition syndromes was based on clinical suspicion prompting referral to a specialized geneticist.However,advances in molecular technologies have led to a shift toward a“genotypefirst”approach.Identification of genetic variants related to cancer predisposition enables tailored treatment,improves clinical outcome,optimizes surveillance,and facilitates genetic counseling of the affected child and the family.

Younger age of onset and multiple primary lesions associated with esophageal squamous cell carcinoma cases with a positive family history of the cancer suggests genetic predisposition

Background Previous epidemiological studies have consistently found a positive family history of esophageal cancer is associated with a significantly increased risk of the cancer.However,whether the elevated risk could be attributed to common household exposure or inherited susceptibility is uncertain.This study aimed to highlight the effect of genetic predisposition by noting the significant differences in onset age and multiple primary cancers between esophageal squamous cell carcinoma （ESCC） cases with or without a positive family history of the cancer.Methods Age at onset and the percentage of multiple primary cancers were compared between ESCCs with （n=766） or without （n=1 776） a positive family history of the cancer in a consecutive surgery cohort at the Department of Thoracic Surgery of Hebei Tumor Hospital and the Fourth Hospital of Hebei Medical University.Results Overall,ESCCs with a positive family history of the cancer featured both a significantly younger age of onset and significantly more multiple primary cancers than those with a negative family history （onset age 51.83 vs.53.49 years old,P 〈0.01; percent of multiple primary cancers 5.50% vs.1.70%,x2=25.42,P 〈0.01）.Both the differences were evident in subgroup analyses,but did not correlate.While age at onset differed significantly by family history among the male,smoking,and drinking groups,the difference of multiple primary cancers was significant among the otherwise nonsmoking,nondrinking,and younger onset age groups.Conclusions Younger age of onset and multiple primary cancers associated with ESCCs with a positive,as opposed to a negative family history of the cancer,suggest a genetic predisposition.The results of subgroup analyses indicate a younger age of ESCC development results from the interaction of environmental and genetic risk factors,but multiple primary cancers may be related only to genetic predisposition.

Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies

Whether Fanconi anemia(FA)heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting.We retrospectively analyzed rare possibly significant variations(PSVs)in the five most obligated FA genes,BRCA2,FANCA,FANCC,FANCD2,and FANCG,in 788 patients with aplastic anemia(AA)and hematologic malignancy.Sixty-eight variants were identified in 66 patients(8.38%).FANCA was the most frequently mutated gene(n=29),followed by BRCA2(n=20).Compared with that of the ExAC East Asian dataset,the overall frequency of rare PSVs was higher in our cohort(P=0.016).BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia(P=0.038),and FANCA PSVs were significantly enriched in AA and AML subgroups(P=0.020;P=0.008).FA-PSV-positive MDS/AML patients had a higher tumor mutation burden,higher rate of cytogenetic abnormalities,less epigenetic regulation,and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients(P=0.024,P=0.029,P=0.024,and P=0.013).The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Germline polymorphisms of circadian genes and gastric cancer predisposition

Dear Editor,Gastric cancer represents a remarkable disease burden worldwide,ranking among the first five tumor types in incidence and mortality[1].Germline DNA variation has been extensively investigated in terms of predisposition to sporadic gastric cancer,which represents more than 90%of all cases[2].Currently available evidence shows that the fraction of disease burden that can be attributable to known risk polymorphisms is small(<20%)[2].Single germline variations of circadian genes(also called clock genes)have been associated with the predisposition of different tumor types[3].The circadian clock is a timetracking rhythmic biological system with a periodicity of about 24 hours that enables organisms to anticipate environmental changes and allow them to modify their behavior and physiological functions in the most efficient way.Circadian rhythms are controlled by proteins encoded by circadian genes,which have been discovered in all studied species.Remarkably,the disruption of these rhythms has been linked with risk of different diseases including cancer.In regards to the latter,a growing wealth of evidence supports the potential tumor suppressor role of the biological clock[3,4].

Germline predisposition to soft tissue sarcoma

Soft tissue sarcoma(STS)most often occurs sporadically,but can also arise in the setting of a germline cancer predisposition syndrome(CPS).There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies,occur in all age groups,and can occur in any location in the body.This diversity is also reflected in the many known associated germline cancer predisposition associations.Some STS diagnoses,such as anaplastic rhabdomyosarcoma,are associated with high heritability and other STS,such as Ewing sarcoma,are notably absent from known CPS.Recognizing when a STS is more likely to be hereditary can influence clinical management.Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection.Additionally,family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies.Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency.This review summarizes current knowledge of selected STS and their associations with CPS.

Hereditary cancer syndromes

Hereditary cancer syndromes(HCSs)are arguably the most frequent category of Mendelian genetic diseases,as at least 2%of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants(PVs).Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity;in addition,there are several dozen less frequent types of familial tumors.The development of the majority albeit not all hereditary malignancies involves two-hit mechanism,i.e.the somatic inactivation of the remaining copy of the affected gene.Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes;however,population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status.Hereditary cancer research initially focused mainly on cancer detection and prevention.Recent studies identified multiple HCS-specific drug vulnerabilities,which translated into the development of highly efficient therapeutic options.

Exposure to Hyaluronan and Radon-Containing Water during the Treatment of Periodontal Pockets

Hyaluronic acid (HA) preparations have emerged as pivotal components in contemporary dentistry, gaining widespread recognition for their multifaceted roles in various biological functions. Extensive literature underscores the significance of HA in maintaining tissue water balance, fostering cell proliferation, promoting rapid cell migration, influencing cell differentiation during organism development, and facilitating tissue regeneration. Notably, HA’s interactions with cell surface receptors contribute to the viscosity of synovial fluid, activate the immune system, and enhance cartilage elasticity. Beyond these established functions, HA has also been investigated for its potential involvement in determining and studying the hormetic effects of radon water, adding a novel dimension to its applications in dental research. A thorough exploration of existing studies reveals a nuanced understanding of how HA interventions impact the outcomes of dental procedures. The comprehensive scope of these investigations allows for a more accurate assessment of the potential effectiveness of specific interventions and provides valuable insights into post-procedural prognoses for individual patients. This synthesis of literature serves as the foundation for elucidating the intricate interplay between HA, radon exposure, and their relevance in modern dental practices.

Micro RNA biomarkers predicting risk,initiation and progression of colorectal cancer

Colorectal cancer is a major global cause of morbidity and mortality. Current strategies employed to increase detection of early,curable stages of this disease are contributing to a reduction of the negative health impact from it. While there is a genetic component to the risk of disease,diet and environment are known to have major effects on the risk of an individual for developing the disease. However,there is the potential to reduce the impact of this disease further b y preventing disease develop ment. Biomarkers which can either predict the risk for or early stages of colorectal cancer could allow intervention at a time when prospects could be modified by environmental factors,including lifestyle and diet choices. Thus,such biomarkers could be used to identify high risk individuals who would benefit from lifestyle and dietary interventions to prevent this disease. This review will give an overview on one type of biomarker in the form of micro RNAs,which have the potential to predict an individual's risk for colorectal cancer,as well as providing a highly sensitive and non-invasive warning of disease presence and/or progression. Micro RNA biomarkers which have been studied and whose levels look promising for this purpose include Mi R-18 a,Mi R-21,Mi R-92 a,Mi R-135 b,Mi R-760,Mi R-601. Not only have several individual micro RNAs appeared promising as biomarkers,but panels of these may be even more useful. Furthermore,understanding dietary sources and ways of dietary modulation of these micro RNAs might be fruitful in reducing the incidence and slowing the progression of colorectal cancer.

Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles

AIM:To evaluate the risk associated with variants of the UNC5C gene recently suspected to predispose to familial colorectal cancer(CRC).METHODS:We screened patients with familial CRC forms as well as patients with sporadic CRCs.In a first time,we analyzed exon 11 of the UNC5C gene in 120unrelated patients with suspected hereditary CRC,58patients with suspected Lynch-associated cancer or polyposis,and 132 index cases of Lynch syndrome families with a characterized mutation in a DNA mismatch repair(MMR).Next,1023 patients with sporadic CRC and1121 healthy individuals were screened for the variants identified in patients with familial cancer.RESULTS:Of 120 patients with familial CRC of unknown etiology,one carried the previously reported mis-sense mutation p.Arg603Cys(R603C)and another exhibited the unreported variant of unknown significance p.Thr617Ile(T617I).The p.Ala628Lys(A628K)mutation previously described as the main UNC5C risk variant for familial CRC was not detected in any cases of familial CRC of unknown etiology,but was present in a patient with familial gastric cancer and in two Lynch syndrome patients in co-occurrence with MMR mutations.A statistically non-significant increase in cancer risk was identified in familial CRC and/or other Lynchassociated cancers(1/178 patients vs 2/1121 healthy controls,OR=3.2,95%CI:0.29-35.05,P=0.348)and in sporadic CRCs(4/1023 patients vs 2/1121 healthy controls,OR=2.2,95%CI:0.40-12.02,P=0.364).CONCLUSION:We confirm that UNC5C mutations are very rare in familial and sporadic CRCs,but further investigations are needed to justify routine UNC5C testing for diagnostic purposes.

Update on diagnosis and management of sepsis in cirrhosis: Current advances

Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis.In cirrhosis,hemodynamic perturbations,immune dysregulation,and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials.Patients with cirrhosis develop recurrent lifethreatening infections that progress to multiple organ failure.The definition,pathophysiology,and treatment options for sepsis have been ever evolving.In this exhaustive review,we discuss novel advances in the understanding of sepsis,describe current and future biomarkers and scoring systems for sepsis,and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis.We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally,propose a treatment algorithm for management of sepsis in patients with cirrhosis.

对上面的胃肠的道的活动性混乱的基因贡献

Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.

Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer(CRC) predisposing genes in early-onset or familial CRC cases.METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with nonpolyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 firstdegree relative diagnosed with CRC at ≤ 55 years of age.Genomic DNA from blood was enriched for exome sequences using the Sure Select Human All Exon Kit, version 2(Agilent Technologies) and sequencing was performed on an Illumina Hi Seq 2000 platform.Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes.RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing.In 6 of the 21 families(29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1(5 patients), MSH2(1 patient), and MUTYH(biallelic, 1 patient), five of which were reported as pathogenic.Inthe remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations.One previously unreported variant identified in a conserved region of EIF2AK4(p.Glu738_Asp739insA rgA rg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy(33.3% vs 7%, P < 0.001).CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.