scholarly journals From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

Breast Care ◽  
2021 ◽  
pp. 1-12
Author(s):  
Emma R. Woodward ◽  
Elke M. van Veen ◽  
D. Gareth Evans
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Reproductive Factors ◽  
Risk Scores ◽  
Clinical Indication ◽  
Nucleotide Polymorphisms ◽  
Moderate Risk ◽  
Risk Genes ◽  
Increased Risk ◽  
Gene Panels

<b><i>Background:</i></b> There has been huge progress over the last 30 years in identifying the familial component of breast cancer. <b><i>Summary:</i></b> Currently around 20% is explained by the high-risk genes <i>BRCA1</i> and <i>BRCA2</i>, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes <i>ATM</i> and<i> CHEK2</i>. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. <b><i>Key-Messages:</i></b> There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as <i>CDH1</i> and <i>TP53</i>, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.

scholarly journals Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families

2021 ◽  
Vol 11 (6) ◽  
pp. 548
Author(s):  
Maria Fonfria ◽  
Inmaculada de Juan Jiménez ◽  
Isabel Tena ◽  
Isabel Chirivella ◽  
Paula Richart-Aznar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Clinical Characteristics ◽  
Single Gene ◽  
Clinicopathological Characteristics ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Risk Genes ◽  
Pathogenic Variants ◽  
Index Cases

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

scholarly journals Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population

2018 ◽  
Vol 91 (2) ◽  
pp. 157-165 ◽  
Author(s):  
Iulian Gabriel Goidescu ◽  
Gabriela Caracostea ◽  
Dan Tudor Eniu ◽  
Florin Vasile Stamatian
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Risk Group ◽  
Deleterious Mutations ◽  
Cancer Genes ◽  
Moderate Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Mutations ◽  
Multigene Panel

Aim. Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing is becoming more common in medical care.We report our experience regarding deleterious mutations of high and moderate-risk breast cancer genes (BRCA1/2, TP53, STK11, CDH1, PTEN, PALB2, CHEK2, ATM), as well as more recently identified cancer genes, many of which have increased risk but less well-defined penetrance.Methods. Genetic testing was performed in 130 consecutive cases with breast cancer referred to our clinic for surgical evaluation and who met the 2016 National Comprehensive Cancer Network (NCCN) criteria for genetic testing.Results. 82 patients had pathogenic/likely pathogenic mutations and VUS mutations, and 48 were negative; 36 of the pathogenic mutations were in the high-risk genes and 16 were in the moderate risk genes and only 5 cases in the intermediary risk group.From the VUS mutation group 21 cases were in the intermediary risk group, 9 cases were in the moderate risk group and only 7 cases in high risk group.The most frequent BRCA1 variant was c.3607C>T (7 cases) followed by c.5266dupC and c.4035delA (each in 4 cases). Regarding BRCA-2 mutations we identified c.9371A>T and c.8755-1G>A in 6 cases and we diagnosed VUS mutations in 3 cases.Conclusion. Our study identified 2 mutations in the BRCA1 gene that are less common in the Romanian population, c.3607C>T and c.4035delA. Both variants had particular molecular phenotypes, c.3607C>T variant respecting the triple negative pattern of BRCA1 breast cancer while c.4035delA were Luminal B HER positive.

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 Can a subgroup at high risk for LRR be identified from T1-2 breast cancer with negative lymph nodes after mastectomy? A meta-analysis

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Gongling Peng ◽  
Zhuohui Zhou ◽  
Ming Jiang ◽  
Fan Yang
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Lymph Nodes ◽  
Patient Population ◽  
Meta Analysis ◽  
Histologic Grade ◽  
Surgical Margins ◽  
Cochrane Library ◽  
Increased Risk ◽  
Negative Lymph Nodes

Abstract Purpose: To identify a subgroup at high risk for loco-regional recurrence (LRR) from T1-2 breast cancer with negative lymph nodes (N0) after mastectomy by using a meta-analysis. Methods and materials: Published studies on the relationship between clinical features and LRR of breast cancer were identified from public databases, including PubMed, EMBASE, and the Cochrane Library. High-risk features for LRR in this patient population were defined based on the pooled results of meta-analysis. Results: For the meta-analysis, a total of 11244 breast cancers with pT1-2N0 after mastectomy from 20 publications were included for analysis. The pooled results indicated that age (hazard ratio (HR) 1.77, P=0.001), lymphovascular invasion (LVI) (HR 2.23, P&lt;0.001), histologic grade (HR 1.66, P&lt;0.001), HER2 status (HR 1.65, P=0.027), menopausal status (HR 1.36, P=0.015), and surgical margins (HR 2.56, P=0.014) were associated with a significantly increased risk of developing LRR in this patient population group, but not for tumor size (HR 1.32, P=0.23), systematic therapy (HR 1.67, P=0.20), and hormonal receptor status (HR 1.04, P=0.73). Conclusion: In the current study, patients with young age, positive LVI, high histologic grade, HER-2 positive, premenopausal, and positive surgical margins have an increased risk of developing LRR. Further prospective trials are needed to clearly define the role of adjuvant postmastectomy radiotherapy in T1-2N0 breast cancer at high risk of developing LRR.

scholarly journals Current and Future Directions of Breast MRI

2021 ◽  
Vol 10 (23) ◽  
pp. 5668
Author(s):  
Margaret Houser ◽  
David Barreto ◽  
Anita Mehta ◽  
Rachel F. Brem
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Digital Breast Tomosynthesis ◽  
Breast Mri ◽  
Preoperative Assessment ◽  
Average Risk ◽  
Dense Breast Tissue ◽  
Increased Risk ◽  
High Risk Populations ◽  
Magnetic Resonance Imaging Mri

Magnetic resonance imaging (MRI) is the most sensitive exam for detecting breast cancer. The American College of Radiology recommends women with 20% or greater lifetime risk of developing breast cancer be screened annually with MRI. However, other high-risk populations would also benefit. Hartmann et al. reported women with atypical hyperplasia have nearly a 30% incidence of breast cancer at 25-year follow-up. Women with dense breast tissue have up to a 4-fold increased risk of breast cancer when compared to average-risk women; their cancers are more likely to be mammographically occult. Because multiple cohorts of women are at high risk for developing breast cancer, there has been a movement to develop an abbreviated MRI (abMRI) protocol to expand the availability of MRI screening. Studies on abMRI effectiveness have been promising, with Weinstein et al. demonstrating a cancer detection rate of 27.4/1000 in women with dense breasts after a negative digital breast tomosynthesis. Breast MRI is also used to evaluate the extent of disease as part of preoperative assessment in women with newly diagnosed breast cancer, and to assess a patient’s response to neoadjuvant chemotherapy. This paper aims to explore the current uses of MRI and propose future indications and directions.

Ancestrally unbiased polygenic breast cancer (BC) risk assessment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10502-10502
Author(s):  
Elisha Hughes ◽  
Placede Tiemeny ◽  
Shannon Gallagher ◽  
Stephanie Meek ◽  
Charis Eng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hereditary Cancer ◽  
Validation Cohort ◽  
Asian Population ◽  
European Ancestry ◽  
Risk Scores ◽  
Published Data ◽  
Nucleotide Polymorphisms ◽  
Cancer History ◽  
Risk Alleles

10502 Background: BC risk is influenced by single-nucleotide polymorphisms (SNPs) with small effects that can be aggregated into polygenic risk scores (PRSs). PRSs have primarily been developed and validated for populations of European descent. To make a PRS available for all women, we developed and validated a novel global PRS (gPRS) that utilizes individual ancestral genetic composition. Methods: Ancestry-specific PRSs corresponding to 3 continental ancestries were developed from 149 SNPs (93 BC and 56 ancestry-informative): an African PRS was developed using a cohort of 31,126 self-reported African American patients referred for hereditary cancer testing; an East Asian PRS was developed based on published data from the Asia Breast Cancer Consortium; and a European PRS was developed using data from the Breast Cancer Association Consortium and 24,259 European hereditary cancer testing patients. For each patient, ancestry-informative SNPs were used to calculate the fractional ancestry attributable to each of the 3 continents. The gPRS was the sum of ancestry specific PRSs weighted according to genetic ancestral composition. In an independent validation cohort (N = 62,707), we evaluated discrimination and calibration of gPRS, and compared performance against a previously described 86-SNP PRS for women of European ancestry. Associations of SNPs and PRSs with BC were analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Odds ratios (ORs) are reported per standard deviation within the corresponding patient population. P-values are reported as two-sided. Results: The gPRS was strongly associated with BC in the full validation cohort and in sub-cohorts defined by self-reported ancestry (Table). 95% (88/93) of BC SNPs had ≥1% frequency of risk alleles within each of the self-reported populations. Compared to the aforementioned 86-SNP PRS, the gPRS showed improved discrimination overall, and within each sub-cohort, with the exception of the Asian population where the sample size was too small to show superiority of either score. The 86-SNP PRS was calibrated for white non-Hispanic women but mis-calibrated for non-European ancestries. The gPRS was properly calibrated for all women. Conclusions: The 149-SNP gPRS is validated and calibrated for women of all ancestries. Combined with clinical and biological risk factors, this approach may offer improved risk stratification for all women, regardless of ancestry.[Table: see text]

scholarly journals Clustering of known low and moderate risk alleles rather than a novel recessive high‐risk gene in non‐ BRCA1 /2 sib trios affected with breast cancer

2020 ◽  
Vol 147 (10) ◽  
pp. 2708-2716
Author(s):  
Florentine S. Hilbers ◽  
Peter J. Hof ◽  
Caro M. Meijers ◽  
Hailiang Mei ◽  
Kyriaki Michailidou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Moderate Risk ◽  
Risk Gene ◽  
Risk Alleles

scholarly journals Diet, menopause and the risk of ovarian, endometrial and breast cancer

2019 ◽  
Vol 78 (3) ◽  
pp. 438-448 ◽  
Author(s):  
Yashvee Dunneram ◽  
Darren C. Greenwood ◽  
Janet E. Cade
Keyword(s):  
Breast Cancer ◽  
Health Outcomes ◽  
Reproductive Factors ◽  
Dietary Factors ◽  
Current Evidence ◽  
Age At Menarche ◽  
Dietary Intakes ◽  
Future Health ◽  
Natural Menopause ◽  
Increased Risk

Menopause, the permanent cessation of the menstrual cycle, marks the end of a woman's reproductive lifespan. In addition to changes in sex hormone levels associated with menopause, its timing is another predictor of future health outcomes such as duration of the presence of vasomotor symptoms (VMS) and the risk of hormone-related cancers. With ageing of the population, it is estimated that worldwide 1·2 billion women will be menopausal by the year 2030. Previously the effects of reproductive factors (e.g. parity, age at menarche, pregnancy) and socio-demographic factors on intermediate and long-term health outcomes of menopause have been widely documented. However, little is known about whether diet could have an impact on these. Therefore, we review current evidence on the associations of diet with menopause, presence of VMS and the risk of hormone-related cancers such as ovarian, endometrial and breast cancer. Dietary factors could influence the lifespan of the ovaries and sex-hormones levels, hence the timing of natural menopause. Few studies reported an association between diet, in particular soya consumption, and a reduced risk of VMS. Sustained oestrogen exposure has been associated with a higher risk of hormone-related cancers and thus high-fat and meat diets have been linked with an increased risk of these cancers. However, to better understand the mechanistic pathways involved and to make stronger conclusions for these relationships, further studies investigating the associations of dietary intakes and dietary patterns with menopause, presence of VMS and the risk of hormone-related cancers are required.

scholarly journals Association of Prolactin and Its Receptor Gene Regions with Familial Breast Cancer

2006 ◽  
Vol 91 (4) ◽  
pp. 1513-1519 ◽  
Author(s):  
Annika Vaclavicek ◽  
Kari Hemminki ◽  
Claus R. Bartram ◽  
Kerstin Wagner ◽  
Barbara Wappenschmidt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Variation ◽  
Receptor Gene ◽  
Academic Research ◽  
Nucleotide Polymorphisms ◽  
Promoter Regions ◽  
Increased Risk ◽  
Human Mammary Tumors ◽  
Variant Alleles

Context: The contribution of prolactin (PRL) through its receptor (PRLR) to the pathogenesis and progression of human mammary tumors has received recent attention. Objective: We investigated whether genetic variation in the PRL and PRLR genes is associated with the risk of breast cancer (BC). Design: We conducted a case-control study with a total of seven single nucleotide polymorphisms (SNPs). Setting: The study was conducted at an academic research laboratory and university clinics. Patients and Other Participants: A total of 441 German familial, unrelated BC cases and 552 controls matched by age, ethnicity, and geographical region participated in the study. Intervention(s): There were no interventions. Main Outcome Measures(s): SNP genotype and haplotype distributions and haplotype interactions were correlated with the risk of BC. Results: Two SNPs (rs1341239 and rs12210179) within the PRL promoter regions were significantly associated with increased risk in homozygotes for the variant alleles [odds ratio (OR), 1.67 and 95% confidence interval (CI), 1.11–2.50; and OR, 2.09 and 95% CI, 1.23–3.52, respectively]. The PRL haplotype containing the variant alleles of the promoter SNPs increased significantly the risk of BC (OR 1.42, 95%CI 1.07–1.90). A PRLR haplotype was associated with a significant decrease in BC risk (OR 0.69, 95% CI 0.54–0.89). An increasing number of PRL and PRLR risk haplotypes led to a significant trend of increasing risk for BC (χ2 = 12.15; P = 0.007). Conclusions: Genetic variation in the PRL and PRLR genes was shown to influence BC risk. Additional studies are needed to further clarify the role of the PRL and PRLR genes in the risk of BC.

Two Single Nucleotide Polymorphisms of the ETS2 Transcriptional Factor Gene Predispose Individuals to High-Risk Acute Myelogenous Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2729-2729
Author(s):  
Il-Kwon Lee ◽  
Jeong-Hwa Choi ◽  
Yeo-Kyeoung Kim ◽  
Hee Nam Kim ◽  
Kyeong-Soo Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
High Risk ◽  
Secondary Structure ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
International Hapmap Project ◽  
Nucleotide Polymorphisms ◽  
Factor Gene ◽  
Increased Risk ◽  
Polymorphic Variants

Abstract ETS2 (v-ets avian erythroblastosis virus E2 oncogene homolog 2) is a transcription factor located in the human chromosomal region 1q22.3 encoding a 56-kDa protein. In this study we carefully selected a set of haplotype-tagging SNPs (htSNP) and genotyped their frequencies in order to identify polymorphic variants that contributes to the inter-individual differences in susceptibility to disease phenotypes. Here we report polymorphisms of ETS2, a hematopoietic transcription factor gene is associated with increased risk to AML. Seven SNPs derived from genomic region of the ETS2 gene, rs1209953, rs3746882, rs2298560, rs457705, rs2070531, rs711 and rs5307 were genotyped to estimate allele frequency, haplotype block and linkage disequilibrium (LD) map. Among those rs711 and rs530 were shown to be associated with increased risk to AML with statistical significance. The odds ratio (OR) for rs711 and rs530 relative to wild type genotypes are 1.76 (95% C.I. 1.2–2.5, p=0.0019) and 1.67 (95% C.I. 1.3–2.2, p=0.0003) respectively. Cumulative frequencies of four common haplotypes are 72%, among which T-T-G-T-C-G-T was the most ancestral haplotype comprising 36% of total haplotypes. We also examined the possibility of haplotype association, but no association was found. When we compared LD map with LDs constructed from the International HapMap project, Korean LD map was similar to Japanese LD, but least similarity was shown with LDs from African(Yoruba in Ibadan, Nigeria). Since these two SNPs are located in the 3′ UTR region we simulated the change in secondary structure in silico of the 3′ UTR region with two variants sequence. Severe change in the secondary structure was observed in the rs530 containing domain suggesting this change might affects stability of mRNA. Real time Q-PCR and western blot revealed that expression of ETS2 decreased in a dosage-dependant manner, showing most abundant expression when homozygously T/T at rs530, least expression with the homozygous A/A and intermediate level of expression when the heterozygous genotype. Our results suggest that polymorphic variants in the 3′ UTR region predispose individual to high-risk AML by altering the secondary structure of mRNA.

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