Inheritance of a Cancer-Associated MLH1 Germ-Line Epimutation
Megan P. Hitchins, Ph.D., Justin J.L. Wong, B.Sc., Graeme Suthers, M.B., B.S., Catherine M. Suter, Ph.D., David I.K. Martin, M.D., Nicholas J. Hawkins, Ph.D., and Robyn L. Ward, Ph.D.
Persons who have hypermethylation of one allele of MLH1 in somaticcells throughout the body (a germ-line epimutation) have a predispositionfor the development of cancer in a pattern typical of hereditarynonpolyposis colorectal cancer. By studying the families oftwo such persons, we found evidence that the epimutation wastransmitted from a mother to her son but was erased in his spermatozoa.The affected maternal allele was inherited by three other siblingsfrom these two families, but in those offspring the allele hadreverted to the normal active state. These findings demonstratea novel pattern of inheritance of cancer susceptibility andare consistent with transgenerational epigenetic inheritance.
Source Information
From the Department of Medical Oncology, St. Vincent's Hospital (M.P.H., J.J.L.W., C.M.S., R.L.W.); the Schools of Medicine (M.P.H., C.M.S., R.L.W.) and Medical Sciences (J.J.L.W., N.J.H.), University of New South Wales; and the Victor Chang Cardiac Research Institute (C.M.S., D.I.K.M.) — all in Sydney; the Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, Australia (G.S.); and the Children's Hospital Oakland Research Institute, Oakland, CA (D.I.K.M.).
Address reprint requests to Dr. Ward at the Department of Medical Oncology, St. Vincent's Hospital, Victoria Street, Darlinghurst, NSW 2010, Australia, or at robyn{at}unsw.edu.au.
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