BackgroundInherited factors predisposing individuals to breast and ovarian cancer are largely unidentified in a majority of families with hereditary breast and ovarian cancer (HBOC). We aimed to identify germline copy number variations (CNVs) contributing to HBOC susceptibility in the Finnish population.MethodsA cohort of 84 HBOC individuals (negative for BRCA1/2-founder mutations and pre-screened for the most common breast cancer genes) and 36 healthy controls were analysed with a genome-wide SNP array. CNV-affecting genes were further studied by Gene Ontology term enrichment, pathway analyses, and database searches to reveal genes with potential for breast and ovarian cancer predisposition. CNVs that were considered to be important were validated and genotyped in 20 additional HBOC individuals (6 CNVs) and in additional healthy controls (5 CNVs) by qPCR.ResultsAn intronic deletion in the EPHA3 receptor tyrosine kinase was enriched in HBOC individuals (12 of 101, 11.9%) compared with controls (27 of 432, 6.3%) (OR = 1.96; P = 0.055). EPHA3 was identified in several enriched molecular functions including receptor activity. Both a novel intronic deletion in the CSMD1 tumor suppressor gene and a homozygous intergenic deletion at 5q15 were identified in 1 of 101 (1.0%) HBOC individuals but were very rare (1 of 436, 0.2% and 1 of 899, 0.1%, respectively) in healthy controls suggesting that these variants confer disease susceptibility.ConclusionThis study reveals new information regarding the germline CNVs that likely contribute to HBOC susceptibility in Finland. This information may be used to facilitate the genetic counselling of HBOC individuals but the preliminary results warrant additional studies of a larger study group.

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

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. INTRODUCTIONBreast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women in both developed and developing countries. Worldwide, 1.67 million new BC cases are diagnosed each year, and the number of BC-related deaths is 522 000. 1 In Finland, BC was diagnosed in 4694 women in 2012, and the annual number of BC diagnoses is predicted to increase (Finnish Cancer Registry). Up to 10% of all BCs are familial. 2 Approximately 20-25% of familial BCs are due to germline variants in two high-risk genes, BRCA1 and BRCA2, which are tumour suppressor genes that encode large proteins that act in a common pathway of genome protection and have important roles at different stages in DNA damage response (DDR) and DNA repair. 3,4 Variant in BRCA1/2 confer a high risk of breast and ovarian cancers; the average cumulative cancer risks in a population-based series of unselected breast or ovarian cancer patients have been estimated to be 65% and 39% for BRCA1 variant carriers and 45% and 11% for BRCA2 variant carriers, respectively, by age of 70. 5 In the Finnish population, the contribution of BRCA1/2 -variants to the breast/ovarian cancer families and ovarian cancer-only families is~20% and 26%, respectively. 6,7 In addition to BRCA1/2, rare germline variants in the known highrisk genes TP53, CDH1, STK11, and PTEN predispose to familial cancer syndromes, among which BC is also observed. 4 Moreover, genes for which their protein products interact with BRCA1/2 in the DDR pathway are strong candidates for breast and/or ovarian cancer

Background BRCA1 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3488-x) contains supplementary material, which is available to authorized users.

We have analyzed the histopathological, clinical, and genetic characteristics in hereditary breast and ovarian cancer patients of counselled families from 1996 up to today in the southwestern Finland population. In this study we analyzed the incidence of different BRCA1 and BRCA2 pathogenic variants (PV). 1211 families were evaluated, and the families were classified as 38 BRCA1 families, 48 BRCA2 families, 689 non-BRCA families and 436 other counselled families (criteria for genetic testing was not met). In those families, the study consisted of 44 BRCA1 breast and/or ovarian cancer patients, 58 BRCA2 cancer patients, 602 non-BRCA patients and 328 other counselled patients. Breast cancer mean onset was 4.6 years earlier in BRCA1 carriers compared to BRCA2 (p = 0.07, a trend) and ovarian cancer onset almost 11 years earlier in BRCA1 families (p < 0.05). In BRCA families the onset of ovarian cancer was later than 40 years, and BRCA2-origin breast cancer was seen as late as 78 years. The BRCA PV (9%) increases the risk for same patient having both ovarian and breast cancer with a twofold risk when compared to non-BRCA group (4%) (95% CI p < 0.05). Triple-negativity in BRCA1 (42%) carriers is approximately 2.6 times vs more common than in BRCA2 carriers (16%) (p < 0.05). The risk ratio for bilateral breast cancer is approximately four times when compared BRCA2 (17%) and other counselled patients’ group (4%) (p < 0.05). 27% southwestern BRCA2-families have a unique PV, and correspondingly 39% of BRCA1-families. The results of this analysis allow improved prediction of cancer risk in high-risk hereditary breast and ovarian families in southwestern Finland and improve long term follow-up programs. According to the result it could be justified to have the discussion about prophylactic salpingo-oophorectomy by the age of 40 years. The possibility of late breast cancer onset in BRCA2 carriers supports the lifelong follow-up in BRCA carriers. Cancer onset is similar between BRCA2 carries and non-BRCA high-risk families. This study evaluated mutation profile of BRCA in southwestern Finland. In this study genotype–phenotype correlation was not found

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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.