scholarly journals Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria

2019 ◽  
Vol 56 (12) ◽  
pp. 838-843 ◽  
Author(s):  
Rosa M Xicola ◽  
Shuwei Li ◽  
Nicolette Rodriguez ◽  
Patrick Reinecke ◽  
Rachid Karam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Cancer Risk ◽  
Pathogenic Variant ◽  
Age At Diagnosis ◽  
Breast Cancers ◽  
Cancer Risks ◽  
Clinical Criteria ◽  
Gastric Cancers ◽  
Risk Of Cancer

BackgroundThe clinical phenotype of CDH1 pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1 pathogenic variants not selected by HDGC clinical criteria.MethodsPatients were all consecutively identified CDH1 pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1 families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.ResultsWithin the 113 CDH1 pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.ConclusionIn unselected CDH1 pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1 testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

scholarly journals Mutations in the BRCA1 gene: implications of inter-population differences for predicting the risk of radiation-induced breast cancers

1998 ◽  
Vol 72 (3) ◽  
pp. 191-198 ◽  
Author(s):  
R. CHAKRABORTY ◽  
K. SANKARANARAYANAN
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Brca1 Gene ◽  
Mutant Gene ◽  
Cancer Predisposition ◽  
Breast Cancers ◽  
Cancer Risks ◽  
Gene Frequencies ◽  
Radiation Induced ◽  
Dose Dependent

The effects of cancer predisposition and increased tumorigenic radiosensitivity of the predisposed genotypes on radiation cancer risks (in the general population and in sisters and first cousins of affected probands) are studied using an autosomal dominant model of cancer predisposition and radiosensitivity. The model assumes that the predisposing alleles, which confer enhanced tumorigenic radiosensitivity, are incompletely penetrant. In addition, the model also allows for sporadic cancers, unrelated to the predisposing locus. The predictions of the model are illustrated using current estimates of BRCA1 mutant gene frequencies; the estimates of the strength of predisposition and radiosensitivity differentials used are based on animal and human studies. It is shown that, unless both the strength of predisposition and radiosensitivity differential are large (say, >100-fold in comparison with normal homozygotes), (i) the effect of risk heterogeneity on cancer risk is marginal; (ii) dose-dependent radiation effect remains virtually the same as in a homogeneous irradiated population that has no predisposed subgroups; (iii) for the same radiation dose, relatives of affected probands show an enhancement of cancer risks; and (iv) most extra cancers in relatives can be attributed to radiosensitivity differentials. This simple model can give an upper bound of the effect of risk heterogeneity on radiation-induced breast cancer risks even when the cumulative breast cancer risk is age-dependent. Further, our model predicts that the benefits of mammography outweigh the risks.

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals The association between XRCC3 rs1799794 polymorphism and cancer risk: a meta-analysis of 34 case–control studies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Weiqing Liu ◽  
Shumin Ma ◽  
Lei Liang ◽  
Zhiyong Kou ◽  
Hongbin Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Thyroid Cancer ◽  
Cancer Risk ◽  
Large Scale ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Cancer Type ◽  
Increased Risk ◽  
Risk Of Cancer

Abstract Background Studies on the XRCC3 rs1799794 polymorphism show that this polymorphism is involved in a variety of cancers, but its specific relationships or effects are not consistent. The purpose of this meta-analysis was to investigate the association between rs1799794 polymorphism and susceptibility to cancer. Methods PubMed, Embase, the Cochrane Library, Web of Science, and Scopus were searched for eligible studies through June 11, 2019. All analyses were performed with Stata 14.0. Subgroup analyses were performed by cancer type, ethnicity, source of control, and detection method. A total of 37 studies with 23,537 cases and 30,649 controls were included in this meta-analysis. Results XRCC3 rs1799794 increased cancer risk in the dominant model and heterozygous model (GG + AG vs. AA: odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.00–1.08, P = 0.051; AG vs. AA: OR = 1.05, 95% CI = 1.00–1.01, P = 0.015). The existence of rs1799794 increased the risk of breast cancer and thyroid cancer, but reduced the risk of ovarian cancer. In addition, rs1799794 increased the risk of cancer in the Caucasian population. Conclusion This meta-analysis confirms that XRCC3 rs1799794 is related to cancer risk, especially increased risk for breast cancer and thyroid cancer and reduced risk for ovarian cancer. However, well-designed large-scale studies are required to further evaluate the results.

Association of APC and MCC Polymorphisms with Increased Breast Cancer Risk in an Indian Population

2011 ◽  
Vol 26 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Nupur Mukherjee ◽  
Nilanjana Bhattacharya ◽  
Satyabrata Sinha ◽  
Neyaz Alam ◽  
Runu Chakravarti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Breast Cancer Patients ◽  
Increased Risk ◽  
Risk Of Cancer

The adenomatous polyposis coli (APC) and mutated in colorectal cancer (MCC) genes are key regulatory genes of the Wnt/β-catenin signaling pathway, which are independently involved in maintaining low levels of β-catenin in the cell. In addition to genetic and epigenetic alterations, some genetic polymorphisms in the genes associated with the Wnt signaling pathway have been reported to be associated with an increased risk of cancer, including breast cancer. In the present study we analyzed the association of genotype and haplotype status of two single nucleotide polymorphisms (SNPs), rs2229992 and rs11283943, in the APC and MCC genes, respectively, with an increased risk of breast carcinogenesis in a breast cancer and control population from eastern India. We observed a significant association of the rs11283943 SNP with increased breast cancer risk. Two specific haplotypes involving the minor allele of rs11283943 were found to be associated with an increased breast cancer risk. Kaplan-Meier curves showed a significant association of the 2–2 genotype (genotype homozygous for the rs11283943 minor allele) with decreased survival (p=0.045) of the breast cancer patients in our study, in particular patients with early-onset BC.

scholarly journals Multipathway risk assessment of trihalomethane exposure in drinking water of Lebanon

2007 ◽  
Vol 5 (4) ◽  
pp. 511-522 ◽  
Author(s):  
Lucy Semerjian ◽  
John Dennis
Keyword(s):  
Cancer Risk ◽  
Tap Water ◽  
Inhalation Exposure ◽  
Dermal Absorption ◽  
Cancer Risks ◽  
Oral Ingestion ◽  
Lifetime Cancer Risk ◽  
Exposed Population ◽  
Total Cancer ◽  
Risk Of Cancer

The toxicological risks and lifetime cancer risks of trihalomethanes through oral ingestion, dermal absorption, and inhalation exposure from tap water in selected regions in Lebanon are estimated. Existing trihalomethane concentrations do not pose any non-carcinogenic and developmental risks in the exposed population via oral ingestion. Among the three pathways, residents have a higher risk of cancer through oral ingestion than through the other two pathways. The lifetime cancer risk through oral ingestion for dibromochloromethane makes the highest contribution to total risks, followed by bromodichloromethane, bromoform, and chloroform. The total multipathway cancer risk analysis suggests that no cancer risks exist during the summer and winter seasons; however, in the spring the total cancer risks exceeds the USEPA acceptable level of 10−6 by a factor of 10.7.

scholarly journals Cancer incidence in people with affective disorder: nationwide cohort study in Taiwan, 1997–2010

2014 ◽  
Vol 205 (3) ◽  
pp. 183-188 ◽  
Author(s):  
Yen-Ni Hung ◽  
Shu-Yu Yang ◽  
Ming-Chyi Huang ◽  
For-Wey Lung ◽  
Shih-Ku Lin ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Major Depression ◽  
Cancer Risk ◽  
Affective Disorders ◽  
Psychiatric Inpatient ◽  
Public Health Problem ◽  
Cancer Risks ◽  
Holistic Approaches ◽  
Risk Of Cancer ◽  
Medical Claims Database

BackgroundCancer is a serious public health problem worldwide, and its relationship with affective disorders is not clear.AimsTo investigate alcohol- and tobacco-related cancer risk among patients with affective disorders in a large Taiwanese cohort.MethodRecords of newly admitted patients with affective disorders from January 1997 through December 2002 were retrieved from the Psychiatric Inpatient Medical Claims database in Taiwan. Cancers were stratified by site and grouped into tobacco- or alcohol-related cancers. Standardised incidence ratios (SIRs) were calculated to compare the risk of cancer between those with affective disorders and the general population.ResultsSome 10 207 patients with bipolar disorder and 9826 with major depression were included. The risk of cancer was higher in patients with major depression (SIR = 2.01, 95% CI 1.85–2.19) than in those with bipolar disorder (SIR 1.39, 95% CI 1.26–1.53). The elevated cancer risk among individuals ever admitted to hospital for affective disorders was more pronounced in tobacco- and/or alcohol-related cancers.ConclusionsElevated cancer risk was found in patients who had received in-patient care for affective disorders. They require holistic approaches to lifestyle behaviours and associated cancer risks.

scholarly journals Considerations When Using Breast Cancer Risk Models for Women with Negative BRCA1/BRCA2 Mutation Results

2019 ◽  
Vol 112 (4) ◽  
pp. 418-422
Author(s):  
Robert J MacInnis ◽  
Yuyan Liao ◽  
Julia A Knight ◽  
Roger L Milne ◽  
Alice S Whittemore ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Invasive Breast Cancer ◽  
Disease Incidence ◽  
Brca2 Mutation ◽  
Estimation Algorithm ◽  
Breast Cancers ◽  
Risk Models ◽  
Replication Studies

Abstract The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%–56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.

scholarly journals Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Clara Bodelon ◽  
Hannah Oh ◽  
Andriy Derkach ◽  
Joshua N. Sampson ◽  
Brian L. Sprague ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Intermediate Step ◽  
Breast Cancers ◽  
Tissue Samples ◽  
Polygenic Risk ◽  
Age Related

Abstract Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

scholarly journals Risk-Reducing Salpingo-Oophorectomy and Breast Cancer Risk Reduction in the Gynecologic Oncology Group Protocol-0199 (GOG-0199)

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Phuong L Mai ◽  
Austin Miller ◽  
Mitchell H Gail ◽  
Steven Skates ◽  
Karen Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Incidence ◽  
Breast Cancer Incidence ◽  
Incidence Rates ◽  
Pathogenic Variant ◽  
Risk Reducing ◽  
Cancer Risk Reduction

Abstract Background Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. Methods We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. Results The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval  = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. Conclusions These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention.

scholarly journals Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention

2020 ◽  
Vol 17 (4) ◽  
pp. 1181 ◽  
Author(s):  
Hannah Lui Park
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Alcohol Consumption ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Hormone Therapy ◽  
Environmental Exposures ◽  
Breast Cancers ◽  
Prevention Strategies ◽  
Epigenetic Biomarkers

Environmental and lifestyle factors are believed to account for >80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies.

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