A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome.
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.
Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia.
Qing
Q
Liu
Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia.
Luke B
LB
Hesson
Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia.
Andrea C
AC
Nunez
Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia.
Deborah
D
Packham
Hereditary Cancer Clinic , Prince of Wales Hospital , Randwick, New South Wales 2031 , Australia and.
Rachel
R
Williams
Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney New South Wales 2052, Australia.|Level 3 Brian Wilson Chancellery, The University of Queensland, Brisbane, Queensland 4072, Australia.
Robyn L
RL
Ward
Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia.
Mathew A
MA
Sloane
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000097:blood / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D018076:DNA, Complementary / Q000097:blood / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005091:Exons; D015321:Gene Rearrangement; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010375:Pedigree; D057345:Sequence Inversion
D018076:DNA, Complementary; D004273:DNA, Neoplasm; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein