Finnish Breast Cancer Families Research Articles

ATM c.7570G>C is a high-risk allele for breast cancer.

ATM is generally described as a moderate-risk breast cancer susceptibility gene. However, some of ATM variants might encounter higher risk. ATM c.7570G>C, p.Ala2524Pro, (rs769142993) is a pathogenic Finnish founder variant causative for recessively inherited ataxia-telangiectasia. At cellular level, it has been reported to have a dominant-negative effect. ATM c.7570G>C has recurrently been described in Finnish breast cancer families and unselected case cohorts collected from different parts of the country, but the rarity of the allele (MAF 0.0002772 in Finns) and lack of confirming segregation analyses have prevented any conclusive risk estimates. Here, we describe seven families from genetic counseling units with ATM c.7570G>C variant showing co-segregation with breast cancer. Further analysis of the unselected breast cancer cohort from Northern Finland (n=1822), a geographical region previously indicated to have enrichment of the variant, demonstrated that c.7570G>C significantly associates with breast cancer, and the risk is estimated as high (odds ratio [OR]=8.5, 95% confidence interval [CI]=1.04-62.46, P=.018). Altogether, these results place ATM c.7570G>C variant among the high-risk alleles for breast cancer, which should be taken into consideration in genetic counseling.

Germline EMSY sequence alterations in hereditary breast cancer and ovarian cancer families

BackgroundBRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease.MethodsIndex individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2.ResultsAltogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory elements. The novel deletion was predicted to affect splicing regulatory elements.ConclusionsThese results suggest that the identified EMSY variants are likely neutral at the population level. However, these variants may contribute to breast/ovarian cancer risk in single families. Additional analyses are warranted for rare novel intronic deletions and the 3'UTR variants predicted to have functional roles.

Whole-exome sequencing of Finnish hereditary breast cancer families.

A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies.

Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families.

The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case–control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26–1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case–control dataset (1.49 [1.38–1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3897-6) contains supplementary material, which is available to authorized users.

ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

Screening of HELQ in breast and ovarian cancer families

Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition, we screened the gene for germline variation in 185 Finnish breast or ovarian cancer families and performed haplotype analyses for 1517 breast cancer cases, 308 ovarian cancer cases, and 1234 population controls using five common polymorphisms at the HELQ gene locus. No truncating mutations were identified among the families. One putatively pathogenic missense mutation c.1309A>G was identified but no additional carriers were observed in the subsequent genotyping of 332 familial breast or ovarian cancer patients. Furthermore, the haplotype distribution did not differ between breast or ovarian cancer cases and population controls. Our results indicate that HELQ is not a major breast and ovarian cancer susceptibility gene in the Finnish population. However, we cannot rule out rare risk-variants in the Finnish or other populations and larger datasets are needed to further assess the role of HELQ especially in ovarian cancer predisposition.

Abstract LB-284: Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families

Abstract Background: Breast cancer has a well-established genetic component. However, genetic predisposition factors remain mostly unresolved in high-risk hereditary breast cancer families that do not carry mutations in two major susceptibility genes, BRCA1 and BRCA2. In this study, we aimed to identify rare variants contributing to disease susceptibility in the high-risk Finnish BRCA1/2-negative hereditary breast or breast-ovarian cancer families by using family-based exome sequencing approach. Methods: Germline DNA of 37 individuals from 13 high-risk hereditary breast or breast-ovarian cancer families was analyzed using targeted exome capture and massively parallel sequencing. Priority was given for rare (minor allele frequency<0.05) coding functional variants including nonsynonymous single nucleotide variants (SNVs), frameshift indels as well as stoploss/stopgain and splice-site variants. Candidate variants were selected based on the computational pathogenicity predictions by several tools and gene pathway analyses. Moreover, segregation of the variants with the disease was studied in the families. Candidate variants were confirmed by Sanger sequencing and genotyped in additional cohorts of breast cancer patients and healthy controls. Results: Altogether 21,530 rare coding functional variants (97.0% nonsynonymous SNVs, 1.6% frameshift indels, 1.4% stoploss/stopgains variants) as well as 5 splice site variants were observed in 37 individuals. Of these, 93 novel variants, that harbor genes participating in the DNA damage response pathway, were prioritized. Furthermore, only variants that were predicted to be pathogenic, were considered and they were manually studied through literature. Altogether 20 candidate variants were selected for further segregation, validation, and genotyping experiments, which are currently ongoing. Conclusions: Identified rare functional variants especially in the DNA damage response pathway genes can explain a fraction of the genetic predisposition to breast and ovarian cancer in the high-risk Finnish families. Citation Format: Kirsi M. Kuusisto, Tommi Rantapero, Minna Kankuri-Tammilehto, Matti Nykter, Satu-Leena Laasanen, Johanna Schleutker. Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-284. doi:10.1158/1538-7445.AM2015-LB-284

RAD51, XRCC3, and XRCC2 mutation screening in Finnish breast cancer families.

Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls. Our results suggest that RAD51, XRCC3, and XRCC2 do not substantially contribute to breast cancer predisposition in the Finnish population.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0880-3) contains supplementary material, which is available to authorized users.

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.

Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.

Evaluation of the RHINO gene for breast cancer predisposition in Finnish breast cancer families

Hereditary predisposition to breast cancer is largely affected by the mutations in the genes of the DNA repair pathways. Novel genes involved in DNA repair are therefore prospective candidates also for breast cancer susceptibility genes. The RHINO (Rad9, Rad1, Hus1-interacting nuclear orphan) gene plays a central role in DNA damage response and in cell cycle regulation. RHINO interacts with Rad9-Rad1-Hus1 (9-1-1) complex and with ATR activator TopBP1, which recruit it to the site of DNA damage. We analyzed the effects of the germline variation in RHINO on breast cancer risk. We sequenced the coding region of the RHINO gene 466 index cases of Finnish breast cancer families and in 507 population controls. The genotypes of the most likely functional variant were further determined in a large dataset of 2,944 cases and 1,976 controls. We analyzed the common variation of the RHINO locus and determined the haplotypes using five SNPs in 1,531 cases and 1,233 controls. We identified seven variants including four missense variations, a 5' UTR variant, a silent variant, and a nonsense variant c.250C>T, R84X (rs140887418). All variants were also present in control individuals with frequencies close to those of the cases (P > 0.05). The c.250C>T variant was present in 12 breast cancer patients (0.4 %) and of 16 controls (0.8 %) with the difference not statistically significant (OR = 0.50, 95 %CI: 0.24-1.06, P = 0.066). The haplotype frequencies did not differ in cases and controls (P = 0.59). Germline variation in the RHINO gene is unlikely to influence inherited susceptibility to breast cancer.

Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families

BackgroundTesting for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT.MethodsThe study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria.ResultOf the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997–2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele.ConclusionsGiven the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.

Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families

BackgroundCurrently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer.MethodsThe entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing.ResultsMutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility.ConclusionsThe present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.

Abstract 5599: Screening for large genomic rearrangements in the FANCA and FANCJ genes reveals extensive genomic FANCA deletion in a Finnish breast cancer family

Abstract A portion of familial breast cancer is accounted for by mutations in the same genes that are inactivated in Fanconi anemia (FA). In the current study we set out to evaluate the role of large genomic rearrangements in the FANCA and FANCJ/BRIP1 genes in Finnish breast cancer families. Mutations in the upstream FANCA gene account for the majority of FA patients, and about one-third of all FANCA mutations are large intragenic deletions. Based on the gene's hypermutable nature, the protein's interaction with BRCA1 and its involvement in genomic integrity maintenance, we considered FANCA as a candidate for breast cancer susceptibility. In FANCJ, which is a downstream FA and known breast cancer susceptibility gene, early truncating mutations have been reported, but no large deletions have been recognized so far. For the present study, blood DNA from affected index persons of 100 Northern Finnish breast cancer families were assessed for possible constitutional exonic deletions or amplifications in FANCA and FANCJ by using the multiplex ligation-dependent probe amplification (MLPA) method. We identified a novel large heterozygous FANCA deletion in one of the studied breast cancer families, removing the promoter region and the first 12 exons of the gene. The defective allele was absent from all of the tested 124 controls as well as 540 unselected breast cancer cases, but was present in the father of the index patient having pancreatic cancer. No large deletions in FANCJ were uncovered. We conclude that large FANCA deletions might contribute to breast cancer susceptibility, therefore more extensive studies on their involvement in the disease are needed. To our knowledge, this is the first report on the existence of a large-size genomic deletion in an upstream FA gene in association with familial breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5599. doi:10.1158/1538-7445.AM2011-5599

Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family

A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer.

Screening for large genomic rearrangements of the BRIP1 and CHK1 genes in Finnish breast cancer families

In search for susceptibility genes that could explain an additional portion of familial breast cancer clustering in Finland, we set out to evaluate the presence of large genomic rearrangements in two candidate genes, BRIP1 and CHK1. BRIP1 is a BRCA1 associated protein that is mutated in a fraction of familial breast cancer and Fanconi anemia cases. To date, the role of large BRIP1 deletions in breast cancer susceptibility is not well-characterized. CHK1 is a critical maintainer of cell cycle checkpoints and genomic stability, and is also involved in the BRCA1 and FA protein signalling pathways. Although CHK1 is a very important protein for cell cycle and DNA integrity maintenance control, no mutations in this gene has yet been associated with predisposition to cancer. For the present study, blood DNA from affected index persons of 111 Northern Finnish breast cancer families was assessed for possible constitutional exonic deletions or amplifications in the BRIP1 and CHK1 genes by using the multiplex ligation-dependent probe amplification method. Our results showed that exonic deletions or amplifications affecting the BRIP1 and CHK1 genes seem not to contribute to hereditary breast cancer susceptibility in the Finnish population. To our knowledge, this is the first attempt to determine the existence of large CHK1 deletions in familial breast cancer or in any disease with a hereditary background.

54 Screening for large genomic rearrangements of the BRIP1 and CHK1 genes in Finnish breast cancer families

54 Screening for large genomic rearrangements of the BRIP1 and CHK1 genes in Finnish breast cancer families

Familial breast cancer screening reveals an alteration in the RAP80 UIM domain that impairs DNA damage response function

Germline mutations in two major susceptibility genes, BRCA1 and BRCA2, account for nearly 20% of familial breast cancers. A majority of the remaining genetic factors involved in heritable breast cancer susceptibility are, however, unknown. Recently, a new BRCA1-interacting protein, receptor associated protein 80 (RAP80), was identified. RAP80 plays an important role in BRCA1-mediated DNA damage responses (DDRs) by recruiting BRCA1 to DNA double-strand breaks (DSBs). A comprehensive screening of DNA from affected index cases of 112 BRCA1/BRCA2 mutation-negative Finnish breast cancer families revealed altogether 10 alterations in RAP80, one of which, c.241-243delGAA, resulted in a single glutamic acid deletion at residue 81 in a highly conserved region of ubiquitin interaction motif 1. The resultant delE81 protein product displayed significantly reduced ubiquitin binding and DSB localization. Expression of the RAP80 delE81 allele impaired both BRCA1 and ABRA1 DSB recruitment, thus compromising BRCA1-mediated DDR signaling. Compared with wild-type RAP80, expression of the delE81 allele was associated with a significant increase in cytogenetically detectable chromosomal aberrations, particularly chromatid breaks. Although evidently quite rare, these results suggest that critical constitutional mutations in RAP80 abrogate DDR function and may be involved in genetic predisposition to cancer.

Rad50 c.687delT Does Not Contribute Significantly to Familial Breast Cancer in a French Population

Mutations in DNA repair genes are known for their association with hereditary breast cancer. BRCA1 and BRCA2 are the major genes for high-penetrance familial breast and ovarian cancer, whereas mutations in ATM or Chek2 confer more modest cancer risk. Additional genes involved in DNA double-strand break repair have more recently been associated with breast cancer risk: heterozygosity for deleterious mutations in components of the Rad50-Mre11-Nbs1 complex seems to predispose to breast cancer. In particular, the c.687delT mutation in Rad50 conferred an odds ratio of 4.3 for the risk of breast cancer in a study of Finnish breast cancer families. To explore the contribution of this mutation to breast cancer in French families for which no BRCA mutation could be found, we analyzed the relevant exon in 618 familial breast cancer cases and 513 controls with no personal or familial history of breast cancer. Rad50 was analyzed in its entirety for 231 familial cases, with no clearly deleterious mutations detected. These data together suggest that although founder mutations may make Rad50 a significant breast cancer risk factor in certain populations, it is not a factor in others.

Evidence against PALB2 involvement in Icelandic breast cancer susceptibility

Several mutations in the PALB2 gene (partner and localizer of BRCA2) have been associated with an increased risk of breast cancer, including a founder mutation, 1592delT, reported in Finnish breast cancer families. Although most often the risk is moderate, it doesn't exclude families with high-risk mutations to exist and such observations have been reported. To see if high-risk PALB2-mutations may be present in the geographically confined population of Iceland, linkage analysis was done on 111 individuals, thereof 61 breast cancer cases, from 9 high-risk non-BRCA1/BRCA2 breast cancer families, targeting the PALB2 region. Also, screening for the 1592delT founder mutation in the 9 high-risk families and in 638 unselected breast cancer cases was performed. The results indicate no linkage in any of the high-risk families and screening for the 1592delT mutation was negative in all samples. PALB2 appears not to be a significant factor in high-risk breast cancer families in Iceland and the 1592delT mutation is not seen to be associated with breast cancer in Iceland.

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

BackgroundBRCA1 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.MethodsAltogether 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.ResultsWe 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.ConclusionIn 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.