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Research: breast cancer

Breast cancer is the most common cancer among women world wide. In the Netherlands breast cancer affects one in nine women and in about 10% of these cases breast cancer predisposition genes play a role. The currently known genes for breast cancer have been subdivided into several risk categories; high, moderate, and low. In 20-25% of familial breast cancer cases a causative germ line mutation can be identified, predominantly in one of the high-risk genes BRCA1 or BRCA2 . Other known high-risk breast cancer genes are TP53 , PTEN , LKB1 / STK11 , and CDH1 / E-cadherin, but mutations in these genes are very rare and cause syndromes that predispose carriers to develop multiple types of tumors. The ATM , CHEK2 , BRIP1 , and PALB2 genes belong to the moderate-risk genes. At least one out of 50 Dutch females with breast cancer carries the 1100delC mutation in CHEK2 . Low-risk alleles are currently subject of intense investigation and are common variants of genes that confer a small increase in breast cancer risk.

 

We study the breast cancer risk in women in the Dutch founder mutation CHEK2*1100delC. In addition, we want to understand the role of CHEK2 and BRCA1 mutations in breast carcinogenesis. For this aim, we use genomic profiling of hereditary breast cancers and functional studies in cell lines with BRCA1 - and CHEK2 mutations. We also use genomic profiling and exome sequencing of hereditary breast tumors to find novel breast cancer susceptibility genes.

Figure 1. mRNA clustering of familial and sporadic breast cancer identifying the ?Intrinsic subtypes?

Figure 2. Mitomycin C induced chromatid breaks in a breast cancer cell lines deficient for the breast cancer susceptibility gene BRCA1

Since BRCA1, BRCA2, BRIP1 and PALB2 are all members of the FA/BRCA-pathway we investigated this pathway in a set of 40 well-characterized breast cance cell lines. Cells with a defect in the FA/BRCA pathway are extremely sensitive to DNA crosslinking agends and show mitomycin C-induced chromitid breaks. We discovered several cell lines with increased chromosomal breakage. This analysis also revealed a number of cell lines with defects in sister chromotid cohesion. Currently, we are studying these cell lines to understand the mechanism of failed genomic maintenance

Key publications

Adank MA, Verhoef S, Oldenburg RA, Schmidt MK, Hooning MJ, Martens JW, Broeks A, Rookus M, Waisfisz Q, Witte BI, Jonker MA, Meijers-Heijboer H. Excess breast cancer risk in first degree relatives of CHEK2 ? 1100delC positive familial breast cancer cases. Eur J Cancer. 49: 1993-1999, 2013.

Bakker JL, van Mil SE, Crossan G, Sabbaghian N, De Leeneer K, Poppe B, Adank M, Gille H, Verheul H, Meijers-Heijboer H, de Winter JP, Claes K, Tischkowitz M and Waisfisz Q. Analysis of the novel Fanconi anemia gene SLX4/FANCP in familial breast cancer cases. Hum Mutat 34: 70-73, 2013

Garcia-Closas M et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet . 45: 392-398, 2013

Michailidou K et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45: 353-361, 2013

Warmoes M, Jaspers JE, Pham TV, Piersma SR, Oudgenoeg G, Massink MP, Waisfisz Q , Rottenberg S, Boven E, Jonkers J, Jimenez CR. Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with potential diagnostic and prognostic value in human breast cancer. Mol Cell Proteomics 11: M111.013334, 2012.

Ghoussaini M, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet . 44: 312-318, 2012.

Adank MA, Jonker MA, Kluijt I, van Mil SE, Oldenburg RA, Mooi WJ, Hogervorst FB, van den Ouweland AM, Gille JJ, Schmidt MK, van der Vaart AW, Meijers-Heijboer H, Waisfisz Q. CHEK2*1100delC homozygosity is associated with a high reast cancer risk in women. J Med Genet. 48: 860-863, 2011.

Adank MA, van Mil SE, Gille JJ, Waisfisz Q, Meijers-Heijboer H. PALB2 analysis in BRCA2-like families. Breast Cancer Res Treat. 127: 357-362, 2011.

Ameziane N, van den Ouweland AM, Adank MA, Vijzelaar RN, Errami A, Dorsman JC, Joenje H, Meijers-Heijboer H, Waisfisz Q. Lack of large genomic deletions in BRIP1, PALB2, and FANCD2 genes in BRCA1/2 negative familial breast cancer. Breast Cancer Res Treat. 118: 651-653, 2009

 

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