A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome

Liu, Qing, Hesson, Luke B., Nunez, Andrea C., Packham, Deborah, Williams, Rachel, Ward, Robyn L. and Sloane, Mathew A. (2016) A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome. Carcinogenesis, 37 1: 10-17. doi:10.1093/carcin/bgv154

Author Liu, Qing
Hesson, Luke B.
Nunez, Andrea C.
Packham, Deborah
Williams, Rachel
Ward, Robyn L.
Sloane, Mathew A.
Title A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome
Formatted title
A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome
Journal name Carcinogenesis   Check publisher's open access policy
ISSN 1460-2180
Publication date 2016-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1093/carcin/bgv154
Open Access Status Other
Volume 37
Issue 1
Start page 10
End page 17
Total pages 8
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted abstract
Lynch syndrome is an autosomal dominant disorder that predisposes carriers of DNA mismatch repair (MMR) gene mutations to early-onset cancer. Germline testing screens exons and splice sites for mutations, but does not examine introns or RNA transcripts for alterations. Pathogenic mutations have not been detected in ~30% of suspected Lynch syndrome cases with standard screening practices. We present a 38-year-old male with a clinicopathological and family history consistent with Lynch syndrome, including loss of MSH2 expression in his tumor. Germline testing revealed normal MSH2 coding sequence, splice sites and exon copy number, however, cDNA sequencing identified an aberrant MSH2 transcript lacking exons 2–6. An inversion PCR on germline DNA identified an ~18kb unbalanced, paracentric inversion within MSH2, with breakpoints in a long terminal repeat in intron 1 and an Alu repeat in intron 6. The 3′ end of the inversion had a 1.2 kb deletion and an 8 bp insertion at the junction with intron 6. Screening of 55 additional Australian patients presenting with MSH2-deficient tumors who were negative in germline genetic tests for MSH2 mutations identified another inversion-positive patient. We propose an Alu-mediated recombination model to explain the origin of the inversion. Our study illustrates the potential value of cDNA screening to identify patients with cryptic MMR gene rearrangements, clarifies why standard testing may not detect some pathogenic alterations, and provides a genetic test for screening individuals with suspected Lynch syndrome that present with unexplained MSH2-deficient tumors.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Office of the Vice-Chancellor
Official 2016 Collection
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
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