Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.

Purpose: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.

Patients And Methods: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay.

Growth and metastatic behavior of molecularly well-characterized human breast cancer cell lines in mice.

Breast cancer (BC) is a disease with intra- and inter-tumor heterogeneity, and models representing the complete variety of clinical BC phenotypes are not available. We explored the tumor growth potential and metastatic behavior of human BC cell lines and determined whether these cell lines can recapitulate subtype-related biological characteristics of tumors. Eighteen human BC cell lines were implanted under the mammary fat pad of nude mice.

Loss of E-cadherin is not a necessity for epithelial to mesenchymal transition in human breast cancer.

Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens.

E-cadherin promotor methylation and mutation are inversely related to motility capacity of breast cancer cells.

Inactivation of the tumor suppressor E-cadherin is an important event during breast tumorigenesis, as its decreased expression is linked to aggressiveness and metastasis. However, the relationship between the different modes of E-cadherin inactivation (mutation versus promotor hypermethylation) and breast cancer cell behavior is incompletely understood. The high correlation between E-cadherin inactivation status and cell morphology in vitro suggests different biological roles for the two inactivation modes during breast tumorigenesis.

MUTYH gene variants and breast cancer in a Dutch case–control study.

The MUTYH gene is involved in base excision repair. MUTYH mutations predispose to recessively inherited colorectal polyposis and cancer. Here, we evaluate an association with breast cancer (BC), following up our previous finding of an elevated BC frequency among Dutch bi-allelic MUTYH mutation carriers.

Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes.

CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors.

Prevalence of the variant allele rs61764370 T>G in the 3'UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families.

Recently, a variant allele in the 3'UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls.

Genome-wide association study identifies five new breast cancer susceptibility loci.

Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls.

Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146.

Most assays to detect circulating tumor cells (CTCs) rely on EpCAM expression on tumor cells. Recently, our group reported that in contrast to other molecular breast cancer subtypes, "normal-like" cell lines lack EpCAM expression and are thus missed when CTCs are captured with EpCAM-based technology [J Natl Cancer Inst 101(1):61-66, 2009]. Here, the use of CD146 is introduced to detect EpCAM-negative CTCs, thereby improving CTC detection.

Discovering moderate-risk breast cancer susceptibility genes.

To date, five moderate-risk breast cancer susceptibility genes have been convincingly identified: CHEK2, ATM, BRIP1, PALB2, and NBS1. Moderate-risk breast cancer alleles confer increased breast cancer risks of two to fourfold compared to the 10% risk in the general population. In contrast to the high-risk BRCA1 and BRCA2 genes, moderate-risk genes typically have a limited number of variants that confer breast cancer risks.

Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer.

Homozygous and compound heterozygous MUTYH mutations predispose for MUTYH-associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer.

Association of rare MSH6 variants with familial breast cancer.

Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes.

Phosphatidylinositol 3-kinase signaling does not activate the wnt cascade.

Mutational activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in a wide variety of tumors, whereas activating Wnt pathway mutants are predominantly found in colon cancer. Because GSK3 is a key component of both pathways, it is widely assumed that active PI3K signaling feeds positively into the Wnt pathway by protein kinase B (PKB)-mediatefd inhibition of GSK3. In addition, PKB has been proposed to modulate the canonical Wnt signaling through direct stabilization and nuclear localization of beta-catenin.

Four human breast cancer cell lines with biallelic inactivating alpha-catenin gene mutations.

Mutations of E-cadherin have been identified in half of lobular breast cancers and diffuse-type gastric cancers, two tumor subtypes with remarkably similar pathological appearances including small rounded cells with scant cytoplasm and a diffuse growth pattern. A causal role for E-cadherin gene mutations in the lobular breast cancer phenotype was recently demonstrated in E-cadherin knock-out mice. These observations suggested that another gene in the E-cadherin tumor suppressor pathway might be mutated in lobular breast cancers with wild-type E-cadherin genes.

Low-risk susceptibility alleles in 40 human breast cancer cell lines.

Background: Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to 1.3 fold.

Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines.

Breast cancer has for long been recognized as a highly diverse tumor group, but the underlying genetic basis has been elusive. Here, we report an extensive molecular characterization of a collection of 41 human breast cancer cell lines. Protein and gene expression analyses indicated that the collection of breast cancer cell lines has retained most, if not all, molecular characteristics that are typical for clinical breast cancers.

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2.

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium.

Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells.

Identification of specific subtypes of circulating tumor cells in peripheral blood of cancer patients can provide information about the biology of metastasis and improve patient management. However, to be effective, the method used to identify circulating tumor cells must detect all tumor cell types. We investigated whether the five subtypes of human breast cancer cells that have been defined by global gene expression profiling-normal-like, basal, HER2-positive, and luminal A and B-were identified by CellSearch, a US Food and Drug Administration-approved test that uses antibodies against the cell surface-expressed epithelial cell adhesion molecule (EpCAM) to isolate circulating tumor cells.

CHEK2 1100delC and male breast cancer in the Netherlands.

Mutations in the breast cancer susceptibility genes BRCA1, BRCA2, and CHEK2 are known risk factors for female breast cancer. Mutations in BRCA1 and BRCA2 also are associated with male breast cancer (MBC). Similarly, it had been suggested in the original CHEK2 identification report that the CHEK2 1100delC mutation confers an increased risk for MBC.

Exon expression arrays as a tool to identify new cancer genes.

Background: Identification of genes that are causally implicated in oncogenesis is a major goal in cancer research. An estimated 10-20% of cancer-related gene mutations result in skipping of one or more exons in the encoded transcripts. Here we report on a strategy to screen in a global fashion for such exon-skipping events using PAttern based Correlation (PAC).

CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer.

Purpose: The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk.

Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines.

The CHEK2 protein plays a major role in the regulation of DNA damage response pathways. Mutations in the CHEK2 gene, in particular 1100delC, have been associated with increased cancer risks, but the precise function of CHEK2 mutations in carcinogenesis is not known. Human cancer cell lines with CHEK2 mutations are therefore of main interest.

Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines.

Constitutive activation of the phosphatidylinositol-3-OH kinase (PI3K) and RAS signaling pathways are important events in tumor formation. This is illustrated by the frequent genetic alteration of several key players from these pathways in a wide variety of human cancers. Here, we report a detailed sequence analysis of the PTEN, PIK3CA, KRAS, HRAS, NRAS, and BRAF genes in a collection of 40 human breast cancer cell lines.