<em>TOPBP1</em>, <em>CLSPN</em> and <em>PALB2</em> genes in familial breast cancer susceptibility

Abstract The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility. In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms. Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles. In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer. The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered

Analysis of large deletions in <it>BRCA1</it>, <it>BRCA2 </it>and <it>PALB2 </it>genes in Finnish breast and ovarian cancer families

Abstract Background BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Methods Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. Results We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. Conclusion In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility.</p

Mutation analysis of the AATF gene in breast cancer families

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RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability

The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P = 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G > A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxyterminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer

RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer