Design and validation of an oligonucleotide microarray for the detection of genomic rearrangements associated with common hereditary cancer syndromes

Journal of Experimental & Clinical Cancer Research

Benjamin Roa¹  Kelsey Moyes¹  Christopher Arnell¹  Jonathan Craft¹  Jayson Holladay¹  Aaron Theisen¹  Natalia Gutin¹  Adam Murray¹  Matthew Ryder¹  Jeremy Schoenberger¹  Collin Burton¹  Nick Woolstenhulme¹  Thaddeus Judkins¹  Debora Mancini-DiNardo¹ 

[1] Myriad Genetic Laboratories, Inc., Salt Lake City 84108, UT, USA

关键词: Genetic screening;    Lynch syndrome;    Hereditary breast and ovarian cancer;    Large genomic rearrangements;    Microarray analysis;   

Others  :  1145590
DOI  :  10.1186/s13046-014-0074-9

 received in 2014-05-22, accepted in 2014-08-29,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Mancini-DiNardo et al.; licnsee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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