Cancer Surveillance in Healthy Carriers of Germline Pathogenic Variants in BRCA1/2: A Review of Secondary Prevention Guidelines

Germline pathogenic alterations in the breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are the most prevalent causes of hereditary breast and ovarian cancer. The increasing trend in proportion of cancer patients undergoing genetic testing, followed by predictive testing in families of new index patients, results in a significant increase of healthy germline BRCA1/2 mutation carriers who are at increased risk for breast, ovarian, and other BRCA-related cancers. This review aims to give an overview of available screening guidelines for female and male carriers of pathogenic or likely pathogenic germline BRCA1/2 variants per cancer type, incorporating malignancies that are more or less recently well correlated with BRCA1/2. We selected guidelines from national/international organizations and/or professional associations that were published or updated between January 1, 2015, and February 1, 2020. In total, 12 guidelines were included. This review reveals several significant discordances between the different guidelines. Optimal surveillance strategies depend on accurate age-specific cancer risk estimates, which are not reliably available for all BRCA-related cancers. Up-to-date national or international consensus guidelines are of utmost importance to harmonize counseling and proposed surveillance strategies for BRCA1/2 carriers.

Download Full-text

Association between Single-Nucleotide Polymorphisms in Breast Cancer Susceptibility Genes and Clinicopathological Characteristics

10.21203/rs.3.rs-33064/v2 ◽

2020 ◽

Author(s):

Kejing Zhang ◽

Lili Tang ◽

Shouman Wang ◽

Yuan Yang ◽

Hao Wang ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Susceptibility ◽

Molecular Subtype ◽

Breast Cancer Susceptibility ◽

Clinicopathological Characteristics ◽

Negative Association ◽

Nucleotide Polymorphisms ◽

Cancer Susceptibility Genes ◽

Increased Risk

Abstract Background: The incidence rate of breast cancer ranks highest in both China and the United States. Understanding the associations between genetic polymorphisms and clinicopathological features of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.The purpose of the present study was to evaluate the associations between seven tagging single nucleotide polymorphisms (tSNPs) and risk of breast cancer assessed by tumor pathological characteristics and body mass index (BMI). Methods: Seven tSNPs of four breast cancer susceptibility genes were analyzed in 734 Chinese women with breast cancer and 672 age-matched healthy controls, then the association with clinicopathological characteristics, BMI, molecular subtype, TNM staging and lymph node status, was determined. Results: Two tSNPs, rs12951053 located in TP53 and rs16945628 in BRIP1, displayed increased risk of breast cancer in the BMI ≧ 25 kg/m2 group (OR=1.50, 95% CI: 1.02-2.21, P=0.041 and OR=1.92, 95% CI: 1.13-3.26, P=0.015, respectively). The other five tSNPs (rs1805812, rs2735385 and rs6999227 in NBS1, rs7220719 in BRIP1 and rs2299941 in PTEN) displayed a decreased risk of breast cancer in the 18.5≤BMI<25 kg/m2 group. Two tSNPs, rs12951053 in TP53 and rs7220719 in BRIP1 exhibited an increased risk of triple‐negative breast cancer(TNBC) (OR=1.50, 95% CI: 1.05-2.15, P=0.026 and OR=2.13, 95% CI: 1.05-4.29, P=0.032, respectively), and the three tSNPs in NBS1 (rs1805812, rs2735385 and rs6999227) all displayed negative association with both luminal B breast cancer and TNBC. The tSNP rs2299941 in PTEN also exhibited a negative association with each breast cancer molecular subtype, except TNBC. The majority of tSNPs displayed a negative association with stage II or III breast cancer. A number of tSNPs showed a negative association with breast cancer that was lymph node negative or with 1-3 positive nodes. Only one tSNP, rs12951053 in TP53 displayed a positive association with lymph node negative breast cancer (OR=1.43, 95% CI: 1.08-1.91, P=0.013). Conclusions: The majority of tSNPs displayed a negative association with breast cancer and only a few tSNPs (rs12951053 in TP53, rs16945628 and rs7220719 in BRIP1) showed an increased risk of breast cancer as defined by clinicopathological characteristics.

Download Full-text

Association Between Single-Nucleotide Polymorphisms in Breast Cancer Susceptibility Genes and Clinicopathological Characteristics

10.21203/rs.3.rs-33064/v1 ◽

2020 ◽

Author(s):

Kejing Zhang ◽

Lili Tang ◽

Shouman Wang ◽

Yuan Yang ◽

Hao Wang ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Susceptibility ◽

Molecular Subtype ◽

Breast Cancer Susceptibility ◽

Clinicopathological Characteristics ◽

Negative Association ◽

Nucleotide Polymorphisms ◽

Cancer Susceptibility Genes ◽

Increased Risk

Abstract Objective The purpose of the present study was to evaluate the associations between seven tagging single nucleotide polymorphisms (tSNPs) and risk of breast cancer assessed by tumor pathological characteristics and body mass index (BMI). Methods Seven tSNPs of four breast cancer susceptibility genes were analyzed in 734 Chinese women with breast cancer and 672 age-matched healthy controls, then the association with clinicopathological characteristics, BMI, molecular subtype, TNM staging and lymph node status, was determined. Results Two tSNPs, rs12951053 located in TP53 and rs16945628 in BRIP1, displayed increased risk of breast cancer in the BMI ≧ 25 kg/m2 group (OR = 1.50, 95% CI: 1.02–2.21, P = 0.041 and OR = 1.92, 95% CI: 1.13–3.26, P = 0.015, respectively). The other five tSNPs (rs1805812, rs2735385 and rs6999227 in NBS1, rs7220719 in BRIP1 and rs2299941 in PTEN) displayed a decreased risk of breast cancer in the 18.5 ≤ BMI < 25 kg/m2 group. Two tSNPs, rs12951053 in TP53 and rs7220719 in BRIP1 exhibited an increased risk of triple-negative breast cancer(TNBC) (OR = 1.50, 95% CI: 1.05–2.15, P = 0.026 and OR = 2.13, 95% CI: 1.05–4.29, P = 0.032, respectively), and the three tSNPs in NBS1 (rs1805812, rs2735385 and rs6999227) all displayed negative association with both luminal B breast cancer and TNBC. The tSNP rs2299941 in PTEN also exhibited a negative association with each breast cancer molecular subtype, except TNBC. The majority of tSNPs displayed a negative association with stage II or III breast cancer. A number of tSNPs showed a negative association with breast cancer that was lymph node negative or with 1–3 positive nodes. Only one tSNP, rs12951053 in TP53 displayed a positive association with lymph node negative breast cancer (OR = 1.43, 95% CI: 1.08–1.91, P = 0.013). Conclusions The majority of tSNPs displayed a negative association with breast cancer and only a few tSNPs (rs12951053 in TP53, rs16945628 and rs7220719 in BRIP1) showed an increased risk of breast cancer as defined by clinicopathological characteristics.

Download Full-text

INHERITED MUTATION IN BRCA1 AND BRCA2 IN BREAST CANCER

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v3i10.585 ◽

2019 ◽

Vol 3 (10) ◽

Author(s):

Diksha Mishra ◽

Savita Kumari ◽

Navneeta R. Kumar

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Brca Mutation ◽

Breast Cancer Susceptibility ◽

Brca1 And Brca2 ◽

Suppressive Function ◽

Cancer Susceptibility Genes ◽

Increased Risk ◽

Tumor Suppressive Function ◽

Damaged Dna

BRCA1 and BRCA2 are unrelated proteins, but both are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA, or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks. If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer. BRCA1 and BRCA2 have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins". The predominant allele has a normal, tumor suppressive function whereas high penetrance mutations in these genes cause a loss of tumor suppressive function which correlates with an increased risk of breast cancer. Keywords: BRCA1; BRCA2; Breast cancer; Mutation; Gene.

Download Full-text

Integrative genomic analysis implicates ERCC6 and its interaction with ERCC8 in susceptibility to breast cancer

Scientific Reports ◽

10.1038/s41598-020-77037-7 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Roxana Moslehi ◽

Hui-Shien Tsao ◽

Nur Zeinomar ◽

Cristy Stagnar ◽

Sean Fitzpatrick ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Susceptibility Genes ◽

Breast Cancer Susceptibility Gene ◽

Genome Wide Association Studies ◽

Integrative Genomics ◽

Moderate Risk ◽

Cancer Susceptibility Genes ◽

Increased Risk

AbstractUp to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10–6) and ERCC8 (p = 4.67 × 10–6) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.

Download Full-text