Design and Validation of an Oligonucleotide Microarray for the Detection of Genomic Rearrangements Associated with Common Hereditary Cancer Syndromes

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2014 Sep 11

PMID 25204323

Citations 5

Authors

Debora Mancini-DiNardo

Thaddeus Judkins

Nick Woolstenhulme

Collin Burton

Jeremy Schoenberger

Matthew Ryder

Adam Murray

Natalia Gutin

Aaron Theisen

Jayson Holladay

Jonathan Craft

Christopher Arnell

Kelsey Moyes

Benjamin Roa

Affiliations

Soon will be listed here.

Abstract

Background: Conventional Sanger sequencing reliably detects the majority of genetic mutations associated with hereditary cancers, such as single-base changes and small insertions or deletions. However, detection of genomic rearrangements, such as large deletions and duplications, requires special technologies. Microarray analysis has been successfully used to detect large rearrangements (LRs) in genetic disorders.

Methods: We designed and validated a high-density oligonucleotide microarray for the detection of gene-level genomic rearrangements associated with hereditary breast and ovarian cancer (HBOC), Lynch, and polyposis syndromes. The microarray consisted of probes corresponding to the exons and flanking introns of BRCA1 and BRCA2 (≈1,700) and Lynch syndrome/polyposis genes MLH1, MSH2, MSH6, APC, MUTYH, and EPCAM (≈2,200). We validated the microarray with 990 samples previously tested for LR status in BRCA1, BRCA2, MLH1, MSH2, MSH6, APC, MUTYH, or EPCAM. Microarray results were 100% concordant with previous results in the validation studies. Subsequently, clinical microarray analysis was performed on samples from patients with a high likelihood of HBOC mutations (13,124), Lynch syndrome mutations (18,498), and polyposis syndrome mutations (2,739) to determine the proportion of LRs.

Results: Our results demonstrate that LRs constitute a substantial proportion of genetic mutations found in patients referred for hereditary cancer genetic testing.

Conclusion: The use of microarray comparative genomic hybridization (CGH) for the detection of LRs is well-suited as an adjunct technology for both single syndrome (by Sanger sequencing analysis) and extended gene panel testing by next generation sequencing analysis. Genetic testing strategies using microarray analysis will help identify additional patients carrying LRs, who are predisposed to various hereditary cancers.

Citing Articles

Bioinformatics-Based Identification of Key Prognostic Genes in Neuroblastoma with a Focus on Immune Cell Infiltration and Diagnostic Potential of VGF.

Guo Q, Xiao Y, Chu J, Sun Y, Li S, Zhang S Pharmgenomics Pers Med. 2024; 17:453-472.

PMID: 39403102 PMC: 11472764. DOI: 10.2147/PGPM.S461072.

Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome.

Pan S, Cox H, Willmott J, Mundt E, Gorringe H, Landon M Front Oncol. 2023; 13:1069467.

PMID: 36793599 PMC: 9923021. DOI: 10.3389/fonc.2023.1069467.

Identifying the hub gene and immune infiltration of osteoarthritis by bioinformatical methods.

Zhao C Clin Rheumatol. 2020; 40(3):1027-1037.

PMID: 32785809 DOI: 10.1007/s10067-020-05311-0.

Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing.

Mancini-DiNardo D, Judkins T, Kidd J, Bernhisel R, Daniels C, Brown K BMC Med Genomics. 2019; 12(1):138.

PMID: 31623605 PMC: 6798444. DOI: 10.1186/s12920-019-0587-3.

Ten hub genes associated with progression and prognosis of pancreatic carcinoma identified by co-expression analysis.

Zhou Z, Cheng Y, Jiang Y, Liu S, Zhang M, Liu J Int J Biol Sci. 2018; 14(2):124-136.

PMID: 29483831 PMC: 5821034. DOI: 10.7150/ijbs.22619.

References

Judkins T, Rosenthal E, Arnell C, Burbidge L, Geary W, Barrus T . Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012; 118(21):5210-6. PMC: 3532625. DOI: 10.1002/cncr.27556. View

Vissers L, Veltman J, Geurts van Kessel A, Brunner H . Identification of disease genes by whole genome CGH arrays. Hum Mol Genet. 2005; 14 Spec No. 2:R215-23. DOI: 10.1093/hmg/ddi268. View

Schouten J, McElgunn C, Waaijer R, Zwijnenburg D, Diepvens F, Pals G . Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002; 30(12):e57. PMC: 117299. DOI: 10.1093/nar/gnf056. View

Wagner A, Barrows A, Wijnen J, Van der Klift H, Franken P, Verkuijlen P . Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet. 2003; 72(5):1088-100. PMC: 1180263. DOI: 10.1086/373963. View

Kovacs M, Papp J, Szentirmay Z, Otto S, Olah E . Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009; 30(2):197-203. DOI: 10.1002/humu.20942. View

Grabowski M, Mueller-Koch Y, Grasbon-Frodl E, Koehler U, Keller G, Vogelsang H . Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet Test. 2005; 9(2):138-46. DOI: 10.1089/gte.2005.9.138. View

Taylor C, Charlton R, Burn J, Sheridan E, Taylor G . Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. Hum Mutat. 2003; 22(6):428-33. DOI: 10.1002/humu.10291. View

Vasickova P, Machackova E, Lukesova M, Damborsky J, Horky O, Pavlu H . High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet. 2007; 8:32. PMC: 1904436. DOI: 10.1186/1471-2350-8-32. View

Redon R, Carter N . Comparative genomic hybridization: microarray design and data interpretation. Methods Mol Biol. 2009; 529:37-49. PMC: 2871310. DOI: 10.1007/978-1-59745-538-1_3. View

10.

Alkan C, Coe B, Eichler E . Genome structural variation discovery and genotyping. Nat Rev Genet. 2011; 12(5):363-76. PMC: 4108431. DOI: 10.1038/nrg2958. View

11.

Albertson D, Pinkel D . Genomic microarrays in human genetic disease and cancer. Hum Mol Genet. 2003; 12 Spec No 2:R145-52. DOI: 10.1093/hmg/ddg261. View

12.

Kastrinos F, Stoffel E . History, genetics, and strategies for cancer prevention in Lynch syndrome. Clin Gastroenterol Hepatol. 2013; 12(5):715-27. PMC: 3995833. DOI: 10.1016/j.cgh.2013.06.031. View

13.

Wang Y, Friedl W, Lamberti C, Jungck M, Mathiak M, Pagenstecher C . Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer. 2002; 103(5):636-41. DOI: 10.1002/ijc.10869. View

14.

Puget N, Torchard D, Lynch H, Feunteun J, Lenoir G, Mazoyer S . A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res. 1997; 57(5):828-31. View

15.

Kanamori M, Sano A, Yasuda T, Hori T, Suzuki K . Array-based comparative genomic hybridization for genomic-wide screening of DNA copy number alterations in aggressive bone tumors. J Exp Clin Cancer Res. 2012; 31:100. PMC: 3576288. DOI: 10.1186/1756-9966-31-100. View

16.

Baudhuin L, Ferber M, Winters J, Steenblock K, Swanson R, French A . Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology. 2005; 129(3):846-54. DOI: 10.1053/j.gastro.2005.06.026. View

17.

Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F . High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1. Clin Genet. 2007; 72(3):199-207. DOI: 10.1111/j.1399-0004.2007.00849.x. View

18.

Palma M, Domchek S, Stopfer J, Erlichman J, Siegfried J, Tigges-Cardwell J . The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res. 2008; 68(17):7006-14. PMC: 2752710. DOI: 10.1158/0008-5472.CAN-08-0599. View

19.

Pino M, Chung D . Application of molecular diagnostics for the detection of Lynch syndrome. Expert Rev Mol Diagn. 2010; 10(5):651-65. PMC: 2929365. DOI: 10.1586/erm.10.45. View

20.

Li D, Hu F, Wang F, Cui B, Dong X, Zhang W . Prevalence of pathological germline mutations of hMLH1 and hMSH2 genes in colorectal cancer. PLoS One. 2013; 8(3):e51240. PMC: 3602519. DOI: 10.1371/journal.pone.0051240. View