Low-penetrance Genes Research Articles

Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk.

Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians' need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management.

A pan-genome method to determine core regions of the Bacillus subtilis and Escherichia coli genomes

Background: Synthetic engineering of bacteria to produce industrial products is a burgeoning field of research and application. In order to optimize genome design, designers need to understand which genes are essential, which are optimal for growth, and locations in the genome that will be tolerated by the organism when inserting engineered cassettes.Methods: We present a pan-genome based method for the identification of core regions in a genome that are strongly conserved at the species level.Results: We show that the core regions determined by our method contain all or almost all essential genes. This demonstrates the accuracy of our method as essential genes should be core genes. We show that we outperform previous methods by this measure. We also explain why there are exceptions to this rule for our method.Conclusions: We assert that synthetic engineers should avoid deleting or inserting into these core regions unless they understand and are manipulating the function of the genes in that region. Similarly, if the designer wishes to streamline the genome, non-core regions and in particular low penetrance genes would be good targets for deletion. Care should be taken to remove entire cassettes with similar penetrance of the genes within cassettes as they may harbor toxin/antitoxin genes which need to be removed in tandem. The bioinformatic approach introduced here saves considerable time and effort relative to knockout studies on single isolates of a given species and captures a broad understanding of the conservation of genes that are core to a species.

PMS2 is the most frequently mutated Lynch syndrome (LS) gene in women with endometrial cancer (EC): what is the role that low penetrance LS genes play in EC?

Objectives: To determine the frequency and spectrum of LS pathogenic variants in EC patients using upfront germline testing for cancer susceptibility. Secondary objectives included determining the sensitivity and specificity of current LS screening. Methods: Women diagnosed with EC were prospectively enrolled at 9 institutions. Clinical germline testing (panel testing for common cancer susceptibility genes) was performed for 840 unselected EC patients between 10/1/2017 and 10/1/2020. Mismatch repair (MMR) IHC, MLH1 methylation status and relevant clinicopathologic data were abstracted from patients’ records. Detailed family history data were obtained for all subjects. Results: Germline testing revealed 26 of 840 EC patients (3.1%) had a pathogenic/likely pathogenic MMR gene mutation. Mutations in PMS2 were most frequent (10/26, 38%), followed by MSH6 (8/26, 31%), MSH2 (6/26, 23%), and MLH1 (2/26, 8%). Mean BMI for PMS2 carriers was greater than other mutation carriers (31.3 vs 27.8). Age at diagnosis was also higher for PMS2 carriers (59 vs 52). IHC combined with MLH1 methylation correctly predicted LS for all MLH1 and MSH2 mutation carriers. For MSH6 and PMS2, IHC and germline mutation status concordance was lower. Only 4/9 (44%) PMS2 carriers had isolated PMS2 loss. IHC was not completed for one PMS2 carrier (insufficient tumor). IHC correctly predicted MSH6 mutations in 7/8 (88%) carriers. Family history did not predict LS for PMS2 carriers: using PREMM5 (LS prediction model), all had low ( Conclusions: This is the largest cohort of prospectively enrolled EC patients to undergo germline genetic testing in an unselected manner, irrespective of patient age, family history or tumor results. It shows that a majority of LS mutations in EC are in the low-penetrance genes, MSH6 and PMS2. PMS2 mutations were the most common, 10/840 (1.2%). Universal screening with IHC would have missed three PMS2 carriers and one MSH6 carrier. Accurate identification of patients with MMR defects is critical not only for identification of LS, but potentially in consideration of treatment options. In the past, ascertainment of LS relied largely on a strong family cancer history, which is most often seen with MLH1 and MSH2 mutations. For all PMS2 carriers in our study, family history was not predictive of LS and the proband's EC diagnosis was the sentinel event leading to a LS diagnosis in the family. Our study may highlight an evolving LS phenotype in which gene/environment interactions are changing. The observation that EC patients with PMS2 mutations have higher BMIs leads us to hypothesize the existence of an obesity-mediated pathway important in PMS2-associated EC. It may be that in the general population, PMS2 mutation carriers face higher risks for EC than colon cancer.

Genetic testing for assessment of lynch syndrome in young patients with polyps

BackgroundRoutine screening for establishing Lynch syndrome (LS) in young individuals diagnosed with adenomas is not recommended due to its low yield, and limited sensitivity of the employment of immunohistochemistry for DNA mismatch-repair proteins on polyps. Hence we aimed to evaluate the yield of germline mutational analysis in diagnosis of LS in a young Israeli cohort with colorectal adenomatous polyps. MethodsData were retrospectively collected on consecutive patients, age ≤ 45 years, who underwent colonoscopy with removal of at least one adenoma during 2015–2020, and subsequently genetic testing by multigene panel or LS-Jewish founder mutation panel. ResultsOverall, 92 patients were included (median age 35 years, range 23–45 years), of whom 79 (85.8%) underwent multigene panel genotyping, and 13 (14.2%) analysis for Jewish founder LS gene mutations. Altogether, 18 patients were identified with pathogenic mutations in actionable genes, including LS-associated genes in 6 (6.5%), BRCA2 in 2 (2.5%), GREM1 in 1(1.2%), and low-penetrance genes- APC I1307K and CHEK2- in 9 (11.4%) patients. Compared with non-LS patients, LS-carriers had a significantly higher median PREMM5 score (2.6 vs. 1.3; P = 0.04). ConclusionsYoung individuals diagnosed with adenomatous polyps should be offered genetic testing when fulfilling clinical guidelines for LS, but weight should also be given to adenoma characteristics in the PREMM5 score.

Investigating autism associated genes in C. elegans reveals candidates with a role in social behaviour.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a triad of behavioural impairments and includes disruption in social behaviour. ASD has a clear genetic underpinning and hundreds of genes are implicated in its aetiology. However, how single penetrant genes disrupt activity of neural circuits which lead to affected behaviours is only beginning to be understood and less is known about how low penetrant genes interact to disrupt emergent behaviours. Investigations are well served by experimental approaches that allow tractable investigation of the underpinning genetic basis of circuits that control behaviours that operate in the biological domains that are neuro-atypical in autism. The model organism C. elegans provides an experimental platform to investigate the effect of genetic mutations on behavioural outputs including those that impact social biology. Here we use progeny-derived social cues that modulate C. elegans food leaving to assay genetic determinants of social behaviour. We used the SAFRI Gene database to identify C. elegans orthologues of human ASD associated genes. We identified a number of mutants that displayed selective deficits in response to progeny. The genetic determinants of this complex social behaviour highlight the important contribution of synaptopathy and implicates genes within cell signalling, epigenetics and phospholipid metabolism functional domains. The approach overlaps with a growing number of studies that investigate potential molecular determinants of autism in C. elegans. However, our use of a complex, sensory integrative, emergent behaviour provides routes to enrich new or underexplored biology with the identification of novel candidate genes with a definable role in social behaviour.

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

Genetic Variation and the Role of Multigene Panel Testing for Hereditary Breast Cancer: A Single-Institution Experience.

BackgroundBreast cancer is the second leading cause of cancer death in women. There are multiple pathogenic mutations in addition to BRCA1/2 that are implicated in causing hereditary breast cancer.Methods and resultsWe conducted a retrospective analysis of 1568 patients with breast cancer diagnosed between January 1, 2015, and December 31, 2018. The age range is 23-87. Among the study population, 26% had genetic testing and 8% of those were found to carry a pathogenic variant, as designated in NCCN (National Comprehensive Cancer Network) Guidelines. Of that 8%, 3.4% were BRCA1 and BRCA2 mutations, and the rest were other prevalent pathogenic variants.DiscussionExpanded panel testing has the potential to increase the detection rate of pathogenic variants compared to testing for BRCA1/2 alone. Diagnostic accuracy of genetic causes of breast cancer has a significant clinical impact on patients and their families in terms of targeted treatment and prevention strategies. There is a strong need for further understanding of genetic patterns and variations in hereditary breast cancer. Awareness of the possibility of moderate to low penetrance genes and variants of uncertain significance (VUS) is important to assist with appropriate genetic counseling. We believe that physicians should consider re-testing with an expanded panel if patients previously had BRCA1 and BRCA2 testings only with a negative result as it may identify additional mutations.

A pan-genome method to determine core regions of the Bacillus subtilis and Escherichia coli genomes

Background: Synthetic engineering of bacteria to produce industrial products is a burgeoning field of research and application. In order to optimize genome design, designers need to understand which genes are essential, which are optimal for growth, and locations in the genome that will be tolerated by the organism when inserting engineered cassettes. Methods: We present a pan-genome based method for the identification of core regions in a genome that are strongly conserved at the species level. Results: We show that the core regions determined by our method contain all or almost all essential genes. This demonstrates the accuracy of our method as essential genes should be core genes. We show that we outperform previous methods by this measure. We also explain why there are exceptions to this rule for our method. Conclusions: We assert that synthetic engineers should avoid deleting or inserting into these core regions unless they understand and are manipulating the function of the genes in that region. Similarly, if the designer wishes to streamline the genome, non-core regions and in particular low penetrance genes would be good targets for deletion. Care should be taken to remove entire cassettes with similar penetrance of the genes within cassettes as they may harbor toxin/antitoxin genes which need to be removed in tandem. The bioinformatic approach introduced here saves considerable time and effort relative to knockout studies on single isolates of a given species and captures a broad understanding of the conservation of genes that are core to a species.

Upfront Multigene Panel Testing for Cancer Susceptibility in Newly Diagnosed Endometrial Cancer Patients: A Prospective Cohort Study

Background: Lynch syndrome (LS) is the most common cause of hereditary endometrial cancer (EC). Screening EC patients for LS varies by institution and current strategies employ tumor testing and/or family history approaches. Ultimately a LS diagnosis is made by genetic testing. In this study, we evaluated upfront multi-gene panel testing (MGPT) in unselected ECs for improved identification of LS and to determine the frequency of pathogenic variants (PVs) in other cancer susceptibility genes (CSGs).  Methods: EC patients were prospectively enrolled at nine Ohio institutions, 10/1/2017 - 12/31/2020. All patients had clinical germline testing for forty-seven CSGs. Mismatch repair (MMR) immunohistochemistry (IHC), MLH1 methylation and clinicopathologic data were abstracted from patients’ records. Detailed family history data were obtained for all subjects.  Findings: 29 of 961 EC patients (3·1%, 95% CI 2·1 – 4·3%) were found to have LS. <i>PMS2</i> PVs were most frequent (11/29), followed by MSH6 (10/29), <i>MSH2</i> (6/29), and  <i>MLH1</i> (2/29). Tumor IHC was concordant for all <i>MLH1</i> and  <i>MSH2</i>, and 9/10 MSH6 heterozygotes. For  <i>PMS2</i>, tumor IHC and germline status concordance was 80% and family history was not predictive of LS. An additional 68 (7·1%) women had likely pathogenic (LP) or PVs in 16 other CSGs. Twenty-one patients had LP/PVs in high penetrance CSGs. Of note, 10 patients (1·04%) had PVs in <i>BRCA1</i> or <i>BRCA2</i>, with a significant excess of type-II ECs among  <i>BRCA</i> heterozygotes.    Interpretation: Prospective MGPT in a large, unselected EC cohort revealed that a majority of LS diagnoses are attributable to low-penetrance genes. MGPT substantially increased LS diagnoses by capturing patients who had equivocal IHC findings or for whom tumor screening was not performed. The finding that 97/961 (10%) women in this cohort have actionable CSG variants supports a role for upfront MGPT for all women with EC.  Funding: This research was funded by an Ohio State University James Comprehensive Cancer Center Statewide Pelotonia Cancer Impact Award. Declaration of Interest: HH is on the scientific advisory boards for Invitae Genetics, Promega, and Genome Medical. HH has stock/stock options in Genome Medical and GI OnDemand, outside of the submitted work. DC is a COVID response consultant for Kane Logistics, he receives honoraria as Deputy Editor of Gynecologic Oncology and as an author for Up to Date, and he also holds patents: 1) “MicroRNA-based methods and compositions for the diagnosis, prognosis and treatment of ovarian cancer using a real-time PCR platform” Patent number 9,499,869 B2, issued November 22, 2016 Cohn DE, Alder HJ, Croce C, Resnick KE; 2) “Chimeric VEGF peptides” Patent number 8,080,253 B2, issued December 20, 2011 Kaumaya PTP, Cohn DE, all outside of the submitted work. JMs wife is employed by Pfizer Inc. JN declares consulting roles for AstraZeneca, Curio, and Clovis Oncology; speakers’ bureau for Clovis oncology and Merck; and has received a research grant from Zodus Medical Inc, all outside of the submitted work. CB has received honoraria as a speaker for OncLive and for an oral boards review course by Perinatal services, outside of the submitted work. SS reports speakers’ bureaus for AstraZeneca and Merck, outside of the submitted work. KR’s partner is SS with previously listed disclosures. PJG received an award from Promega, outside of the submitted work. MDL, RP, CC, AC, AS, DB, SW, SA, EJ, AC, and RN declare no competing interests. Ethical Approval: The study was approved by the Institutional Review Boards (IRBs) at each participating center with OSU serving as IRB of record.

Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk.

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

Breast Cancer-Related Low Penetrance Genes.

Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.

The results of multigene panel sequencing in Slovak HBOC families.

Hereditary breast and ovarian cancer (HBOC) is primarily associated with mutations in the BRCA1/2 genes. However, causal variants in other high, moderate, and low penetrance genes proportionally increase the risk of breast/ovarian cancer. This study aims to provide data about the mutation spectrum of HBOC-associated genes in Slovak HBOC families and estimate the ratio of BRCA versus non-BRCA causal variants. We used panel sequencing containing 22 high/moderate-risk susceptibility genes and parallel MLPA analysis of BRCA1/2, CHEK2 genes, to analyze 94 individuals with a strong family/personal history of breast and/or ovarian cancer. The analyzed group consisted of 80 patients diagnosed with cancer (85.1%) and 14 healthy individuals (14.9%) with a positive family history of HBOC syndrome. In total, we have identified 22 causal DNA variants (23.4%) showing 15 primary findings in BRCA1/2 genes (68.2%) and 7 positive secondary findings in CHEK2, PALB2, CDH1, and MUTYH genes (31.8%). The most frequent pathogenic alterations were BRCA1 mutations c.181T>G and CNV variant (c.5573-?_c.5701+?)del, known as deletion of exons 21-22. Besides known mutations, the BRCA1 variant c.2794del (p.Val932Leufs*68) and variant c.2480dup (p.Tyr827*) in the CDH1 gene represent the novel, previously unpublished variants that might be population-specific. In conclusion, we provide the first report of multigene panel testing in Slovak HBOC families demonstrating that almost one-third of pathogenic mutations are situated in susceptibility genes other than BRCA1/2. Although multigene panel testing requires precise data filtration and interpretation, it might bring the relevant data for clinical management of the patients.

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals

PurposeTo measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. MethodsWe used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. ResultsOne in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. ConclusionMedically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

ASSOCIATION OF GENOTYPES OF POLYMORPHISMS OF GENES FGFR2, LSP, AND LOC643714 WITH THE RISK OF A POSITIVE MUTATIONAL STATUS OF THE HER-2/NEU GENE IN BREAST CANCER PATIENTS

Breast cancer is the result of genetic and environmental factors that lead to the accumulation of mutations in key regulatory genes. Genetic predisposition to cancer pathologies may be due to mutations in individual genes, such as in BRCA1 and BRCA2, or may be due to a cumulative effect as a result of the interaction of genes of low penetrance. This paper reviews the alleles that determine the risk of high and low penetrance breast cancer and discusses ongoing efforts to identify additional susceptibility genes. The identification of propensity genes is a prerequisite for an individualized assessment of breast cancer risk and a decrease in the incidence of breast cancer. The main goal of this study is to determine the associations of polymorphic variants rs2981582 and rs1219648 of FGFR2, rs3817198 of LSP and rs3803662 of LOC643714 with the risk of breast cancer and the development of a positive mutational status of Her-2/neu. The study group included 300 women diagnosed with breast cancer. Fluorescent in situ hybridization was performed on tumor tissue materials from these patients to determine the amplification status of the Her-2/neu. The distribution of genotypes and alleles was performed by real-time polymerase chain reaction for the following polymorphic variants rs1219648 of FGFR2 (n = 44), rs2981582 of FGFR (n = 99), rs3817198 of LSP1 (n = 75) and rs3803662 of the LOC643714 (n = 82). Among the studied genotypes of polymorphic variants rs3817198 of LSP1, rs3803662 of LOC643714, rs2981582 and rs1219648 of FGFR2, with the inclusion of the risk allele, the association of the propensity to develop breast cancer in women according to the multiplicative model of inheritance (p> 0.05) was not determined. According to the codominant inheritance model, there is an associative relationship with the risk of breast cancer and polymorphism rs3817198 of LSP1, rs3803662 of LOC64371 and rs2981582 of FGFR2 with homozygous genotypes for rare alleles (p <0.05). Women with a positive amplification status of the Her-2/neu, patients with breast cancer, were more likely to carry the risk allele G (OR = 4.80; 95% CI 1.21–28.04, p <0.05) and genotype GG ( OR = 5.82; 95% CI 1.38-16.74, p <0.05) rs3803662 polymorphism of LOC643714, compared with a group of women with negative amplification status of Her-2/neu in patients diagnosed with breast cancer. The results of this study can be useful for searching for additional genetic predictors of breast cancer and a positive mutational status of Her-2/neu.

Morphological and molecular heterogeneity of epithelial ovarian cancer: Therapeutic implications

Ovarian epithelial cancer (OEC) is the most lethal gynecologic malignancy. Despite current chemotherapeutic and surgical options, this high lethality can be attributed to multiple factors, including late-stage presentation. In order to optimize OEC treatment, it is important to highlight that it is composed of five main subtypes: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian carcinoma (EOC), ovarian clear cell carcinoma (CCOC), and mucinous ovarian carcinoma (MOC). These subtypes differ in their precursor lesions, as well as in epidemiological, morphological, molecular and clinical features. OEC is one of the tumours in which most pathogenic germline mutations have been identified. Accordingly, up to 20% OC show alterations in BRCA1/2 genes, and also, although with a lower frequency, in other low penetrance genes associated with homologous recombination deficiency (HRD), mismatch repair genes (Lynch syndrome) and TP53. The most important prognostic factor is the 2014 FIGO staging, while older age is also associated with worse survival. HGSOC in all stages and CCC and MOC in advanced stages have the worse prognosis among histological types. Molecular markers have emerged as prognostic factors, particularly mutations in BRCA1/2, which are associated with a better outcome. Regarding treatment, whereas a proportion of HGSOC is sensible to platinum-based treatment and PARP inhibitors due to HRD, the rest of the histological types are relatively chemoresistant. New treatments based in specific molecular alterations are being tested in different histological types. In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations.

DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India.

Identification of modifier genes predisposing to breast cancer (BC) phenotype remains a significant challenge and varies with ethnicity. The genetic variability observed in DNA repair genes may modulate the cell's ability to repair the damaged DNA and hence, evaluation of genetic variants in crucial DNA damage repair genes is of clinical importance. We performed the present study to evaluate the role of ERCC2-Lys751Gln, hOGG1-Ser326Cys, and XRCC1-Arg399Gln gene polymorphisms on the risk of BC development and its molecular profile in Indian women. Three non-synonymous variants (rs13181, rs1052133, and rs25487) were genotyped in 464 BC patients and 450 healthy controls. Logistic regression was employed to evaluate the association of genotypes with BC risk. Also, in silico analysis was carried out to map the Arg399Gln variant on the BRCT1 domain of XRCC1 protein. XRCC1 Gln/Gln genotype frequency was significantly elevated in BC patients [odd ratio (OR) = 1.73; 95% confidence interval (CI) = 1.13-2.65]. No significant association was observed between hOGG1-Ser326Cys and ERCC2-Lys751Gln variants and BC risk. Subgroup analysis revealed that ERCC2-Lys751Gln and XRCC1-Arg399Gln variants contributed towards tumor progression. A positive interaction between the investigated SNPs and BC was revealed by MDR analysis. Arg399Gln variant resulted in a change in the surface charge of XRCC1 protein. The rs25487 variant of XRCC1 might be associated with an elevated risk of BC. Furthermore, we demonstrated that high order gene-gene interaction plays a significant role in BC etiology. Hence, understanding the impact of low penetrant gene polymorphisms might enable a better understanding of the genetic background of breast cancer.

Gene Mutations in Hereditary Breast Cancer- A Review

The most prevalent form of cancer in females is breast cancer. Roughly 5%-10% of breast cancers are hereditary, and they are associated with Germline gene mutations, inherited from parents. Germline gene mutations increase the risk of developing cancer earlier in life compared to noninherited cases (sporadic cancer). BRCA1 and BRCA2 are well-studied tumour suppressor genes associated with hereditary breast cancer. Even though mutations in BRCA1 and BRCA2 are assumed to responsible the majority of hereditary breast cancers cases, many other breast cancer susceptibility genes have been identified in the last few decades. Identification of many germline mutations was possible due to advance sequencing technologies. Most of these genes are belongs to tumour suppressors and DNA damage repair gene families (DNA double-strand break repair and DNA mismatch repair). These genes play a vital role in genomic stability and cell cycle control suggesting that any alteration in these genes trigger uncontrolled growth and tumour formation. These genes are categorized according to the penetrance level, the proportion of carriers express the associated trait of the mutated gene. Mutations in high penetrance genes such as BRCA1, BRCA2, TP53, PTEN, and SKT11 greatly increase the risk of developing breast cancer. Moderate penetrance gene such as PALB2, ATM, CHEK2, BARD1, BRIP1 and low penetrance gene such as PARP4, CASP8, TOX3 confer moderate to low increase risk of developing breast cancer. Aim of this review is to summarize genes associated with hereditary breast cancer according to their penetrance level (high, moderate and low penetrance).

Modulatory Role of Single Nucleotide Polymorphisms of Distinct Genetic Pathways on Clinical Behavior of Medullary Thyroid Carcinoma.

Role of RET proto-oncogene as predisposing gene for Medullary Thyroid Carcinoma is well established which provides the basis for clinical management of patients. However clinical behavior of MTC varies considerably among patients. Several studies have investigated whether SNPs in low penetrance genes could modulate the clinical behavior of MTC but with conflicting or inconclusive results. The present study aimed to investigate the modifier effect of 13 SNPs of three distinct genetic pathways -Detoxification, Cell cycle regulation and RET on the clinico-pathological features of hereditary and sporadic MTC. SNPs were genotyped using RFLP or TaqMan method. The genotypes were correlated with various clinico-pathological parameters (age and calcitonin levels at MTC diagnosis, tumor volume, nodal and distant metastasis). Nodal metastasis was the only clinico-pathological parameter showing significant association with any SNP. In the hereditary MTC group (n=77), incidence of nodal metastases was significantly higher in wild type allele for Cyp1A1m1, CDKN2A and CDKN2C (p=0.01 for all three). In sporadic MTC group (n=361) CDKN2C wild type allele had higher nodal metastasis (p=0.03). In this largest MTC cohort with comprehensive analysis of modulatory role of 13 most frequently studied SNPs with MTC clinical outcome, we observed a statistically significant association of few SNPs with nodal metastasis. However as these SNPs did not show association with any other clinico-pathological parameters like tumor volume or Calcitonin, they may not be true modifier of MTC. Additional large cohort studies with clinico-pathological details and long-term follow-up are needed to identify genetic modifiers of MTC behavior.

Frequency of mutations in BRCA genes and other candidate genes in high-risk probands or probands with breast or ovarian cancer in the Czech Republic.

Breast cancer is currently the most common form of malignant tumour in womenboth in the Czech Republic and in most countries of the western world, and its incidence is constantly increasing. Many risk factors are known to play a major role in the development of this form of cancer. One of them is genetics, especially the BRCA1/2 genes. A higher risk of ovarian cancer is also associated with these genes. With the development of laboratory diagnostics massive parallel sequencing methods (NGS) are now routinely employed, enabling the detection of other pathogenic sequence variants, or variants of uncertain significance (VUS) not previously detected. Besides the high penetrance BRCA1/2 genes, medium and low penetrant genes also come to the fore. There were 2046 probands examined in the study, men and women, mainly from eastern part of the Czech Republic. These were selected for a genetic examination, after meeting indication criteria (probands from high-risk families or with breast or ovarian cancer). From this group only women, 2033 probands, were selected and were given a genetic examination for the possible presence of patogenic sequence variants in BRCA1/2 genes, or other candidate genes. Analyses were conducted in the laboratory using DHPLC or next generation sequencing. MLPA method is used for large rearrangements in genes. From all examined women 212 mutations were detected. The most mutations (128) were found in the BRCA1 gene (60%). In the BRCA2 gene 71 mutations (34%) were found and 13 more mutations (6%) were detected in another candidate genes (CHEK2, PALB2, ERCC4). The most frequent sequence variant was c.5266dupC in the BRCA1 gene. The results show that 72% of women with a confirmed mutation in the BRCA1 gene and 77.5% of women with the sequence variant BRCA2, already had breast cancer and 16.4% of women with BRCA1 and 7% of women with BRCA2 already had ovarian cancer. Only 21 high risk families used the possibility to be tested and had undergone targeted mutation testing. The study results suggest a reflection of the causes and needs for examination of patients and women predisposed to breast or ovarian cancer.

Update Breast Cancer 2020 Part 1 - Early Breast Cancer: Consolidation of Knowledge About Known Therapies.

This review is intended to present the latest developments in the prevention and treatment of early breast cancer. The risk of breast cancer can be increasingly better characterised with large epidemiological studies on genetic and non-genetic risk factors. Through new analyses, the evidence for high-penetrance genes as well as for low-penetrance genes was able to be improved. New data on denosumab and atezolizumab are available in the neoadjuvant situation as is a pooled appraisal of numerous studies on capecitabine in the curative situation. There is also an update to the overall survival data of pertuzumab in the adjuvant situation with a longer follow-up observation period. Finally, digital medicine is steadily finding its way into science. A recently conducted study on automated breast cancer detection using artificial intelligence establishes the basis for a future review in clinical studies.