Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer

Kuusisto, Kirsi M.; Akinrinade, Oyediran; Vihinen, Mauno; Kankuri-Tammilehto, Minna; Laasanen, Satu-Leena; Schleutker, Johanna

doi:10.1371/journal.pone.0071802

Cited by 28 publications

(40 citation statements)

References 40 publications

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“…There are rare CNVs that are associated with early familial onset of breast cancers devoid of mutations of BRCA1/BRCA2 [64]. In individuals with familial BRCA1/2-negative breast and ovarian cancer, a CNV at 3p11.1 affects carcinogenesis; an intronic deletion in the EPHA3 receptor tyrosine kinase increases the fulminating risk of the disease (OR = 1.96) [65]. The deletion variant of a CNV at 8p22 including mitochondrial tumor suppression gene 1 (MTUS1) also decreases the risk for familial breast cancer [66].…”

Section: Breast Cancermentioning

confidence: 99%

CNVs Associated with Susceptibility to Cancers: A Mini-Review

Furuya¹,

Suehiro²,

Namiki³

et al. 2015

JCT

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Copy number variations (CNVs) that are frequent in genome influence on susceptibility of various diseases including cancers. The present mini-review focuses on CNVs associated with susceptibility to the cancers. Since CNVs are different between cancer types, the analysis of the specific CNV makes it possible to estimate the susceptibility to the cancers of interest in individuals. Although it is true that available data on CNVs associated with cancer susceptibility are limited at present, accumulation of the data is accelerated with the research progression of CNVs in near future. Information on CNVs associated with cancer susceptibility is useful for not only cancer research but also personalized healthcare including cancer prevention.

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Section: Breast Cancermentioning

confidence: 99%

CNVs Associated with Susceptibility to Cancers: A Mini-Review

Furuya¹,

Suehiro²,

Namiki³

et al. 2015

JCT

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“…Recently, rare CNVs were shown to be important sources for interindividual variations in the susceptibility to familial BC [Gonzalez et al, 2005;Krepischi et al, 2012b;Pylkas et al, 2012;Kuusisto et al, 2013;Masson et al, 2014;Park et al, 2015]. Further, we have demonstrated that copy-neutral losses of heterozygosity are also an important class of structural variations and serve as biomarkers of prognostic value in a BC setting [Sapkota et al, 2013a].…”

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confidence: 79%

“…The disease results from the combined effects of genetic, environmental, reproductive, and lifestyle risk factors [Sehrawat et al, 2011; Sapkota et al, 2013a, b]. Single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS) helped explain only a small proportion of genetic risk in BC [Stacey et al, 2007[Stacey et al, , 2008Kidd et al, 2008;Krepischi et al, 2012a;Kuusisto et al, 2013;Long et al, 2013;Michailidou et al, 2013;Sapkota et al, 2013bSapkota et al, , 2014. It is believed that additional variants need to be Key Words Association study · BRCA · Breast cancer susceptibility · Copy number variations · Copy number variation calling algorithm · Genetic predisposition · Germline DNA · Polygenic disease · Single nucleotide polymorphism · Sporadic breast cancer Abstract Breast cancer (BC) predisposition in populations arises from both genetic and nongenetic risk factors.…”

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confidence: 99%

“…The platform technologies also varied (Illumina, Affymetrix Cyto 2.7 M array, Agilent aCGH) as well as CNV calling algorithms (Agilent, Affymetrix, Nexus, Illumina) [Zhang et al, 2011;Krepischi et al, 2012a;Pylkas et al, 2012;Kuusisto et al, 2013;Masson et al, 2014], making it difficult to compare the signatures across all these studies. Rare CNVs identified to date in familial BC showed little overlap between studies [Krepischi et al, 2012b;Kuusisto et al, 2013;Masson et al, 2014], underscoring the need for large-scale replication studies and further development of robust CNV calling algorithms. The identified common CNV associations described in the present study may help to warrant further work to extend the premise that understanding the heritable nature of BC susceptibility in populations may also reside outside of SNP-based association-mapping strategies.…”

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confidence: 99%

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A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Sapkota

Narasimhan

Kumaran

et al. 2016

Cytogenet Genome Res

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Breast cancer (BC) predisposition in populations arises from both genetic and nongenetic risk factors. Structural variations such as copy number variations (CNVs) are heritable determinants for disease susceptibility. The primary objectives of this study are (1) to identify CNVs associated with sporadic BC using a genome-wide association study (GWAS) design; (2) to utilize 2 distinct CNV calling algorithms to identify concordant CNVs as a strategy to reduce false positive associations in the hypothesis-generating GWAS discovery phase, and (3) to identify potential candidate CNVs for follow-up replication studies. We used Affymetrix SNP Array 6.0 data profiled on Caucasian subjects (422 cases/348 controls) to call CNVs using algorithms implemented in Nexus Copy Number and Partek Genomics Suite software. Nexus algorithm identified CNVs associated with BC (731 autosomal CNVs with >5% frequency in the total sample and Q < 0.05). Thirteen CNVs were identified when Partek algorithm-called CNVs were overlapped with Nexus-identified CNVs; these CNVs showed concordances for frequency, effect size, and direction. Coding genes present within BC-associated CNVs were known to play a role in disease etiology and prognosis. Long noncoding RNAs identified within CNVs showed tissue-specific expression, indicating potential functional relevance of the findings. The identified candidate CNVs warrant independent replication.

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“…individuals collected from Tampere University Hospital in which index patients have been screened for variants in BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 genes and for copy number variations on a genome-wide scale. 10,11 In one of these families, two CHEK2 variants, c.470T4C and c.1100delC, have been reported. 10 Seven other families were selected into this study based on the previously described high-risk hereditary BC criteria.…”

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing of Finnish hereditary breast cancer families

et al. 2016

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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

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Copy Number Variation Analysis in Familial BRCA1/2-Negative Finnish Breast and Ovarian Cancer

Cited by 28 publications

References 40 publications

CNVs Associated with Susceptibility to Cancers: A Mini-Review

CNVs Associated with Susceptibility to Cancers: A Mini-Review

A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

Whole-exome sequencing of Finnish hereditary breast cancer families

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