Journal article

Germline and Tumor Sequencing as a Diagnostic Tool To Resolve Suspected Lynch Syndrome

Bernard J Pope, Mark Clendenning, Christophe Rosty, Khalid Mahmood, Peter Georgeson, Jihoon E Joo, Romy Walker, Ryan A Hutchinson, Harindra Jayasekara, Sharelle Joseland, Julia Como, Susan Preston, Amanda B Spurdle, Finlay A Macrae, Aung K Win, John L Hopper, Mark A Jenkins, Ingrid M Winship, Daniel D Buchanan



Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene m..

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Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by NHMRC Senior Research Fellowship

Awarded by NIH National Cancer Institute

Awarded by Colon Cancer Family Registry centers: Australasian Colorectal Cancer Family Registry NCI/NIH

Funding Acknowledgements

Supported by National Health and Medical Research Council of Australia (NHMRC) project grant GNT1125269 (D.D.B.); an NHMRC R.D. Wright Career Development Fellowship (D.D.B.); the University of Melbourne Research at Melbourne Accelerator Program (D.D.B.); a State of Victoria Department of Health and Human Services Victorian Health and Medical Research Fellowship (B.J.P.); a Government of Australia Research Training Program scholarship (P.G.); NHMRC Senior Research Fellowship ID1061779 (A.B.S.); NIH National Cancer Institute award UM1CA167551 (M.A.J.); and cooperative agreements with the following Colon Cancer Family Registry centers (project C-AU-1014-01): Australasian Colorectal Cancer Family Registry NCI/NIH grants U01 CA074778 (M.A.J.) and U01/U24 CA097735 (M.A.J.); and the Victorian Cancer Registry.