Investigation Of Genetic Factors Research Articles

Investigation of Genetic Factors and Clinical Data in Breast Cancer Highlights the Importance of Breastfeeding and Cancer History.

Breast cancer (BC) is the type of neoplasm that most affects women worldwide. It is known that one of the hallmarks of cancer is the resistance to cell death with the evasion of apoptosis. Considering the relevance of TP53, BCL2, CASP3, and CASP9 genes for the occurrence of the intrinsic apoptosis, this study investigated the distribution of the genetic variants rs17880560 (TP53), rs11269260 (BCL2), rs4647655 (CASP3), rs4645982, and rs61079693 (CASP9), as well as genetic ancestry and clinical data, in a BC cohort from the Brazilian Amazon that other variants in these genes might play a role in this process. In the present study, 22 breast cancer tissues and 10 non-cancerous tissues were used, therefore, 32 samples from different patients were subjected to genotyping. We observed that breastfeeding and cancer history were factors that need to be considered for BC (p = 0.022). Therefore, this study contributed to a greater understanding of intrinsic apoptosis in BC, reinforcing previous data that suggest that the history of cancer might be a condition that affects the development of BC and that breastfeeding may act as a protective factor for this type of cancer. We recommend more studies on the genetic factors investigated here, aiming at a future with tools that can help in the early diagnosis.

Abstract 2204: Spectrum of pathogenic germline mutations in Chinese head and neck cancer patients through next-generation sequencing

Abstract Background: Head and neck cancer is currently a leading cause of cancer-associated mortality worldwide. Despite the increasing evidences of variants that were associated with head and neck cancer risk, investigations of genetic factors and their roles in genetic susceptibility to head and neck cancer were limited. The purpose of this study is to assess the inherited genetic factors regarding germline mutations in Chinese head and neck cancer population. Methods: Genomic profiling of DNA was performed through a next-generation sequencing (NGS) (panel on 381/733-gene) on tissue from Chinese patients with head and neck cancer between January 06, 2017 and June 02 2020. TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Results: Of 357 patients with head and neck cancer, 325 (91.04%) patients were identified to carry 457 pathogenic or likely pathogenic germline mutations in 88 cancer predisposition genes, with a frequency of 91.09% (91/101) in nasopharyngeal carcinoma, and 91.41% (234/256) in non-nasopharyngeal carcinoma of the head and neck. In head and neck cancer patients, the most frequently germline mutated genes were CYP2C19 (56.92%), followed by DPYD (37.85 %), CYP2D6 (31.69%), RAC1 (29.85%), VEGFA (29.85%), MGMT (28%), CD74 (24.31%), BCL2L11 (11.69%), and APC (6.46%). Of all the 88 germline mutated genes, 27.27% (n=24) lay in the DNA damage repair (DDR) pathways. The highest frequency of DDR germline mutations was BARD1 (6.15%), followed by BRCA2 (6.15%), PLAB2 (5.54%), FANCD2(5.23%), ATM(4.92%), FANCA (4.62%), RAD50 (4.62%), BRCA1(3.69%), MSH2 (3.38%), and MLH1 (3.08%). Of the 89 nasopharyngeal carcinoma patients with germline mutations that could be evaluated for MSI and TMB, only 1 (1.12%) patient was identified as MSI-H, and 3 (3.37%) patients had TMB≥10Muts/Mb. PD-L1 status analysis was performed in 77 nasopharyngeal carcinoma patients with germline mutated genes, and the results showed that 63 (81.81%) patients were PD-L1 positive (CPS≥1). In non-nasopharyngeal carcinoma with germline mutated genes, MSI status analysis was performed in 228 patients, and the results showed that 2 (0.87%) patient was identified as MSI-H. In addition, 108 (108/198, 27.6%) patients were PD-L1 positive (CPS≥1). Of the 229 non-nasopharyngeal carcinoma that could be evaluated for TMB, 54 (23.58%) patients had TMB≥10Muts/Mb. Conclusions: Taken together, we have presented the spectrum of pathogenic germline mutations in a Chinese head and neck cancer cohort. The findings of inherited genetic variations may provide clues for the oncology treatment strategy and cancer prevention. Citation Format: Jianming Gao, Yating Zheng, Wenzhuan Xie, Mengli Huang. Spectrum of pathogenic germline mutations in Chinese head and neck cancer patients through next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2204.

Glucocorticoid regulation and neuroanatomy in fragile x syndrome

Fragile X syndrome (FXS) is the leading known inherited cause for intellectual disability. Due to mutations in the FMR1 gene, affected individuals are at risk for serious cognitive and behavioral symptoms and developmental disability. Clinical presentation varies considerably, and investigation of genetic factors not directly related to FMR1 may help better understand variability. The present study examined the BclI polymorphism of the glucocorticoid receptor gene NR3C1 in 43 individuals with FXS (28 females, age 16 to 25). Females with FXS who presented with one or more G alleles demonstrated attenuated symptoms of anxiety/depression (p = 0.038) and externalizing behaviors (p = 0.042) relative to individuals with the C/C allele. In the combined sample (males and females) structural neuroimaging data differentiated individuals with a G allele from those with the C/C genotype (p < 0.001). Key components of anxiety/fear neurocircuitry (amygdala, insula) contributed more (relative to other regions) to the model differentiating groups. These results indicate that GR polymorphisms are associated with an altered pattern of behavioral and brain development in FXS. This information is important for understanding and treating mood disorders and altered brain development among individuals with FXS. With further research, these findings could be informative for understanding anxiety and mood disorders more broadly.

Whole genome sequencing of familial isolated oesophagus atresia uncover shared structural variants

BackgroundOesophageal atresia (OA) is a life-threatening developmental defect characterized by a lost continuity between the upper and lower oesophagus. The most common form is a distal connection between the trachea and the oesophagus, i.e. a tracheoesophageal fistula (TEF). The condition may be part of a syndrome or occurs as an isolated feature. The recurrence risk in affected families is increased compared to the population-based incidence suggesting contributing genetic factors.MethodsTo gain insight into gene variants and genes associated with isolated OA we conducted whole genome sequencing on samples from three families with recurrent cases affected by congenital and isolated TEF.ResultsWe identified a combination of single nucleotide variants (SNVs), splice site variants (SSV) and structural variants (SV) annotated to altogether 100 coding genes in the six affected individuals.ConclusionThis study highlights rare SVs among candidate gene variants in our individuals with OA and provides a gene framework for further investigations of genetic factors behind this malformation.

Spectrum of Pathogenic Germline Mutations in Chinese Lung Cancer Patients through Next-Generation Sequencing.

Lung cancer is currently a leading cause of cancer-associated mortality worldwide. Despite the increasing evidences of variants that were associated with lung cancer risk, investigations of genetic factors and their roles in genetic susceptibility to lung cancer were limited. Here we systematically investigated the spectrum of pathogenic germline mutations in Chinese population with lung cancer. Genomic profiling of DNA was performed through next-generation sequencing (NGS) on tissue biopsy from 1764 Chinese lung cancer patients with a 381 cancer gene panel between January 01, 2017 and May 07, 2019. Patients with germline mutations were identified, and their clinical information were collected. Of 1764 patients with lung cancer, 67 (3.8%) patients were identified to carry pathogenic or likely pathogenic germline mutations in 25 cancer predisposition genes, with a frequency of 3.6% in lung adenocarcinoma (49/1349), 4.3% in squamous cell lung cancer (14/322), 5.6% in small cell lung cancer (4/72), and none in lung adenosquamous carcinoma (0/21), respectively. The highest pathogenic germline mutational prevalence were found in BRCA2 (0.79%), CHEK2 (0.40%), BRCA1 (0.34%), and TP53 (0.34%). Two splice mutations were reported for the first time in this study. Notably, a majority (85.5%) of the detected germline mutations fell in DNA damage repair pathways.

52P - Spectrum of pathogenic germline mutations in Chinese lung cancer patients through next-generation sequencing

BackgroundLung cancer is currently a leading cause of cancer-associated mortality worldwide. Despite the increasing evidences of cancer-related variants that were associated with lung cancer risk, investigations of genetic factors and their roles in genetic susceptibility to lung cancer were limited. MethodsGenomic profiling of DNA was performed through next-generation sequencing (NGS) on tissue or liquid biopsy from 3,651 Chinese patients with lung cancer between January 01, 2017 and May 07, 2019 in 3D Medicines database. Patients with germline mutations were identified, and their clinical information were collected. ResultsOf 3,651 patients with lung cancer, 58 (1.59%) were identified to carry one pathogenic germline mutations in 14 potentially cancer predisposition genes, with a frequency of 1.45% in lung adenocarcinoma (N=2837), 1.96% in squamous cell lung cancer (N=612), and 3.12% in small cell lung cancer (N=160), respectively. None has been found in the small subset of adenosquamous lung carcinoma (N=42). Amongst all, the highest mutation prevalence was found in BRCA2 (0.47%), BRCA1 (0.22%), CHEK2 (0.22%), TP53 (0.19%), and RAD50 (0.11%). Notably, a majority (57.1%) of the detected germline mutations fell in DNA damage repair (DDR) pathways, including BRCA2, BRCA1, CHEK2, RAD50, ATM, ATR, PALB2, and MRE11A. No significant correlation of the germline mutation prevalence and patients’ histology type was observed (P=0.26). ConclusionsThis is the first systematic study in germline mutations in Chinese patients with sporadic lung cancer. Our study uncovered the mutation spectrum in Chinese lung cancer population and provided valuable clues for the assessment of the genetic susceptibility to lung cancer. Legal entity responsible for the studyFirst Affiliated Hospital of Army Military Medical University. FundingHas not received any funding. DisclosureY. Zhang: Full/Part-time employment: 3D Medicines Inc. Z. Zhao: Full/Part-time employment: 3D Medicines Inc. S. Cai: Full/Part-time employment: 3D Medicines Inc. All other authors have declared no conflicts of interest.

T24 - Sex-Specific Dna Methylation Signatures In Panic Disorder

Background Panic disorder (PD) is characterized by sudden episodes of acute anxiety occurring without any apparent reason. PD is the most disabling anxiety disorder and it affects twice as many women as men. The heritability of PD is estimated to be up to 48% and epidemiological studies show that both cumulative and specific life events are risk factors for the development of PD. Therefore, the investigation of genetic factors and gene-environment interaction is of high importance for understanding the pathophysiology of PD. As such, examining epigenetic differences in PD patients is of great interest given that environmental factors, in combination with genetic variation, can influence DNA methylation. Methods We conducted an Epigenome-Wide Association Study (EWAS) comparing non-medicated PD patients (49 females, 40 males) with healthy controls (48 females, 28 males). Replication was sought in an independent sample (131 cases, 190 controls) and further confirmed with a meta-analysis across both samples (220 cases, 266 controls). DNA methylation levels were assessed in whole blood using the Infinium HumanMethylation450 BeadChip. Failed probes were excluded based on a detection p-value larger than 0.01 in >50% of the samples. X chromosome, Y chromosome and non-specific binding probes were removed. The data were normalized with functional normalization in Minfi and batch-corrected using ComBat. Regression analyses accounting for cellular heterogeneity, sex and age were performed to test for associations between PD status and DNA methylation. To further assess functionality of the significant CpG, gene expression profiles (Illumina HumanHT-12 v3.0 array) in peripheral blood before and after exposure to the glucocorticoid receptor agonist dexamethasone were tested for association with DNA methylation in another independent female sample (N=71). Results No genome-wide associations were observed in PD patients compared to controls in the whole sample. Interestingly when stratified by sex, only the comparison of female PD patients with controls yielded one genome-wide association surviving FDR of 5% (P= 1.094 x 10-7 , P-adj=0.046). Specifically, cg07308824, located in the promoter of the HECA gene, was hypermethylated in female PD patients (N=49) compared to controls (N=48). The same CpG was also hypermethylated in female PD patients in the replication sample (P=0.035) and the genome-wide significant association was confirmed in the meta-analysis (P-adj=0.007). Methylation at this CpG site was associated with mRNA expression of HECA both at baseline (P= 0.046) and after induction by dexamethasone (P= 0.029). Pathway analyses using Web Gestalt investigating the top 50 associated CpG sites showed enrichment in female-specific pathways, e.g. female infertility pathways. Discussion Our study is the first to examine epigenome wide differences in peripheral blood for PD patients. Interestingly, our results point to possible sex-specific and functional methylation changes in PD. Further studies are needed to examine a possible contribution of the HECA gene methylation to female specific factors in PD.

Abstract A03: Immunoglobulin heavy chain usage in canine CLL

Abstract Canine B cell chronic lymphocytic leukemia resembles human CLL in presentation and clinical outcomes. The disease is indolent (median survival greater than 1000 days) and presents in older dogs (median age = 10.8 years). Major differences between the human and canine disease include immunophenotype (canine B cell CLL does not express CD5) and a gender ratio in the dog that is 1:1. Risk factors for canine B cell CLL have not been identified, but three breeds are more frequently represented amongst CLL cases than in the general population of dogs with confirmed or suspected lymphoproliferative disease of any type; Boxers, Shih-tsu dogs and English Bull dogs. Remarkably, the breed which most frequently develops a variety of lymphoproliferative disorders, the Golden Retriever, is virtually absent from the population of canine CLL patients. This breed predilection suggests that as in people, genetic factors contribute significantly to risk. We hypothesized that canine B cell CLL would be a useful model for uncovering genetic risk factors for the disease, and here we report initial characterization of this model by examining immunoglobulin V gene usage and mutation status. Our findings are: 1) 34% of dogs with CLL had unmutated IgVH genes, as defined by a difference of greater than 2% from the available germline sequence, 2) While the canine genome has 85 IgH V gene segments (43 pseudogenes, 42 functional genes), almost half (42%) of the CLL cases with unmutated IgH genes used a single V gene segment, VH41; Only 9% of non-neoplastic B cells utilize VH41, and 5% of CLL cases with mutated genes use VH41; 3) All animals of the Boxer breed had unmutated IgH genes; 4) canine VH35 was used in 29% of cases with somatic hypermutation, but was not found in unmutated CLL nor in the normal canine B cell repertoire. The striking breed association and restricted V gene usage suggest that certain dog breeds such as the Boxer could provide a useful model for investigation of genetic factors leading to B cell CLL in both humans and dogs. Note: This abstract was not presented at the conference. Citation Format: Robert Burnett, Stacey George, Serena Mancha, Julia Bromerek, Anne Avery. Immunoglobulin heavy chain usage in canine CLL. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A03.

The contribution of epigenetics to understanding genetic factors in autism

Autism spectrum disorder is a grouping of neurodevelopmental disorders characterized by deficits in social communication and language, as well as by repetitive and stereotyped behaviors. While the environment is believed to play a role in the development of autism spectrum disorder, there is now strong evidence for a genetic link to autism. Despite such evidence, studies investigating a potential single-gene cause for autism, although insightful, have been highly inconclusive. A consideration of an epigenetic approach proves to be very promising in clarifying genetic factors involved in autism. The present article is intended to provide a review of key findings pertaining to epigenetics in autism in such a way that a broader audience of individuals who do not have a strong background in genetics may better understand this highly specific and scientific content. Epigenetics refers to non-permanent heritable changes that alter expression of genes without altering the DNA sequence itself and considers the role of environment in this modulation of gene expression. This review provides a brief description of epigenetic processes, highlights evidence in the literature of epigenetic dysregulation in autism, and makes use of noteworthy findings to illustrate how a consideration of epigenetic factors can deepen our understanding of the development of autism. Furthermore, this discussion will present a promising new way for moving forward in the investigation of genetic factors within autism.

Opioid sensitivity in mice selectively bred to consume or not consume methamphetamine.

There has been little investigation of genetic factors and associated mechanisms that influence risk for development of methamphetamine (MA) dependence. Selectively bred mouse lines that exhibit high (MAHDR) or low (MALDR) levels of MA intake in a two-bottle choice MA drinking (MADR) procedure provide a genetic tool for this purpose. These lines were used to determine whether opioid sensitivity and MA intake are genetically associated, because opioid-mediated pathways influence some effects of MA. Sensitivity to the analgesic effects of the μ-opioid receptor (MOP-r) agonist fentanyl (0.05, 0.1, 0.2, 0.4 mg/kg) was examined using two acute thermal tests (hot plate and tail flick) and one chronic pain test (magnesium sulfate abdominal constriction). Locomotor stimulant responses to fentanyl (0.05, 0.1, 0.2, 0.4 mg/kg) and morphine (10, 20, 30 mg/kg) were also examined. In addition, MADR was measured in the progenitor strains [(C57BL/6J (B6), DBA/2J (D2)] of the F2 population from which the selected lines were generated. The MADR lines did not differ in sensitivity to the analgesic effects of fentanyl; however, MALDR mice exhibited greater locomotor activation than MAHDR mice to both fentanyl and morphine. D2 mice consumed more MA than B6 mice. The line differences for MA consumption and morphine activation recapitulated B6 and D2 strain differences for these two traits, but not strain differences previously found for opioid analgesic responses. These results support a negative genetic correlation between MA consumption and sensitivity to the stimulant effects of opioids and suggest the involvement of MOP-r regulated systems in MA intake.

Gene Polymorphisms as Markers of Disease Susceptibility

Gene Polymorphisms as Markers of Disease SusceptibilityThe most widespread diseases of modern man have a polygenic basis, including genetic predisposition and factors in the external environment. Such is the case with cardiovascular disease, malignancy, diabetes and so on. It should be borne in mind that risk factors usually include disorders that are themselves multifactorial, which further indicates the complexity of pathophysiological mechanisms. In the investigation of genetic factors in polygenic diseases studies are underway to determine the association with specific gene polymorphisms. Genetic or DNA polymorphisms are differences in the hereditary basis which are normally found in human populations. The human genome consists of 3×109nucleotide (base) pairs, and it is considered that, on average, every 1000th nucleotide is polymorphic, i.e. varies between two loci or two individuals. The most common type of gene polymorphisms is the single nucleotide polymorphism (SNP). Although gene polymorphisms are an expression of normal variations in the hereditary basis, their effect on the phenotype is interesting, especially the association with proneness to certain diseases. Association studies examine the incidence of certain genetic variants, i.e. genetic polymorphisms in a group of patients, and compare it with the data of a healthy population. The results are often contradictory, so the number of polymorphisms whose role as markers of genetic predisposition has been clearly confirmed is still small. In this paper we review literature data and present experiences from our laboratory in studying genetic polymorphisms as susceptibility factors for the occurrence of thrombophilia and atherosclerosis and its clinical manifestations.

Depression and Coronary Heart Disease: More Pieces of the Puzzle

Depression and Coronary Heart Disease: More Pieces of the Puzzle

Family History and the Risk of Kidney Cancer: a Multicenter Case-control Study in Central Europe

An elevated familial relative risk may indicate either an important genetic component in etiology or shared environmental exposures within the family. Incidence rates of kidney cancer are particularly high in Central Europe, although no data were available on the familial aggregation or genetic background of kidney cancer in this region. We have, therefore, investigated the role of family history in first-degree relatives in a large multicenter case-control study in Central Europe. A total number of 1,097 cases of kidney cancer and 1,555 controls were recruited from 2000 to 2003 from seven centers in Czech Republic, Poland, Romania, and Russia. The risk of kidney cancer increased with the increasing number of relatives with history of any cancer [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.00-1.31 per affected relative], and this association seemed to be more prominent among subjects with young onset (OR, 1.55; 95% CI, 1.09-2.20 per affected relative). Overall, the OR was 1.40 (95% CI, 0.71- 2.76) for the subjects who had at least one first-degree relative with kidney cancer after adjusting for tobacco smoking, body mass index, and medical history of hypertension, and this association was most apparent among subjects with affected siblings (OR, 4.09; 95% CI, 1.09-15.4). Based on the relative risk to siblings in our study population, we estimated that 80% of the kidney cancer cases are likely to occur in 20% of the population with the highest genetic risk, which indicate the importance of further investigation of genetic factors in cancer prevention for kidney cancer.

Applying genetic approaches to the treatment of nicotine dependence.

To advance the science of tobacco control, an enhanced understanding of the bio-behavioral basis of nicotine addiction is needed. In this study, we provide an overview of data from investigations of genetic factors in smoking behavior, discuss potential bio-behavioral mechanisms and effect modifiers, and suggest avenues for pharmacogenetics research in the area of smoking cessation treatment. The evidence to date is very consistent with respect to the significance of genetic contributions to smoking behavior. However, attempts to elucidate the role of specific genetic variants have met with mixed success. Explanations for the lack of consistency in the results of genetic association studies include biases in ascertainment, ethnic admixture, lack of attention to co-variates or modifiers of genetic risk, and the need for more refined phenotypes. As the field of genetics and smoking research progresses, increasing attention is being devoted to gene-environment interactions, with particular attention to the identification of genetic variants that may modify the effects of pharmacological treatment for smoking. With advances in molecular biology and genomics technology, individualized tailoring of smoking cessation therapy to genotype is within our grasp. Such research has the potential to improve treatment outcome, thereby reducing morbidity and mortality from smoking-related disease.

Studies of Genetic Factors in Prostate Cancer in a Twin Population

It has been suggested that positive family history constitutes a risk factor for the development of prostate cancer. Familial clustering of prostate cancer might suggest that genetic factors are of importance in the etiology of this disease. To elucidate further the relative importance of genetic factors, we studied prostate cancer among an unselected Swedish twin population. Information from the Swedish Twin Registry and the Swedish Cancer Registry was used. In 4,840 male twin pairs 458 prostate cancers were identified between 1959 and 1989. Among these 16 monozygotic and 6 dizygotic twin pairs were concordant for prostate cancer. Proband concordance rates of 0.192 and 0.043, and a correlation of liability of 0.40 and −0.05 were found for monozygotic and dizygotic pairs, respectively. These differences in proband concordance rates and correlations of liability for monozygotic pairs compared to dizygotic pairs are pronounced. The results indicate that genetic factors might be of importance for the development of prostate cancer. The results of this study indicate the need for further investigations of genetic factors in prostate cancer, including large scale epidemiological studies and investigations of molecular genetics of risk families.

Psychoses, intracranial neoplasms, and genetics.

The nature of the association between the ABO blood groups and disease is being investigated in the population of the State of Iowa.1The demonstration of statistically significant associations between the ABO blood groups and several diseases suggests that the ABO blood groups may be a tool useful in investigation of genetic factors in still other disorders. This paper is a report of the findings in patients with psychoses and intracranial neoplasms (brain tumors). Materials and Methods The ABO blood types of the patients resident in Mount Pleasant and Independence Mental Health Institutes were determined by the research team, using a slide technique. The patient's blood type, diagnosis, and other relevant information abstracted from the patient's chart were recorded on punch cards. The diagnoses had previously been established by staff members of the Mental Health Institutes and were based upon the standard nomenclature of mental disorders recommended by the