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We have had two international collaborative group meetings on familial MM that culminated in the publication of a multi-center study in the Journal of Clinical Oncology (reprint attached), which describes some 39 MM families.
We now have close to 100 MM families and have recently added collaboration with colleagues at the University of Arkansas School of Medicine, a center of expertise on MM, who are providing additional familial
aggregations of MM for which I am analyzing the pedigrees.
We are also extending these pedigrees to include cancer of all anatomic sites, in addition to MM, with intent to identify patterns of integral tumor combinations with MM. Stephan Thome, M.D., a collaborator, and I have been communicating with Kenneth Offit, M.D., from Sloan-Kettering regarding this issue. We are not yet in a position to characterize fully the phenotypic and genotypic heterogeneity of familial MM, but we do have families that show rather strong associations between MM and other hematologic cancers, as well as families with carcinoma of the breast, malignant melanoma, and pancreatic cancer.
We anticipate continued expansion of this project, and we are securing DNA from living patients affected with MM and their primary relatives, in addition to slides and tissue blocks for collaborative studies with Drs. Weisenburger and Sanger. We have also initiated molecular genetic collaborations with Albert de la Chapelle, M.D., Ph.D., and Carlo Croce, M.D., who are at Ohio State University School of Medicine in the Division of Genetics.
Project 2: Lynch-syndrome-like families without MMR germline mutations
The second project involves the study of families that fulfill the Amsterdam criteria for Lynch syndrome but where no MMR germline mutation has been identified. Recent studies, one from the Mayo Clinic and one from Spain, have identified a cohort of families with phenotypes that fulfill the Amsterdam criteria but are unlike classical Lynch syndrome kindreds in that they have a lesser expression of early-onset colorectal cancer and of cancer of extracolonic sites that are more typical for classical Lynch syndrome. This “new cancer cluster” (syndrome(s) merits more extensive investigation from the clinical as well as the molecular genetic standpoint. We have a large resource of genetically tested, histologically verified, and extended Lynch syndrome and Lynch syndrome-like kindreds of which a subset includes at least 30 families that are comparable to this non-Lynch syndrome model and lack a MMR mutation. We plan to more fully investigate these families, including the collection of DNA from buccal smears, or blood, whichever is most convenient, to be used for linkage analysis in the search for cancer susceptibility loci.
From the cancer family history information on these kindreds that we already have in our data base, we will search for patterns of tumor combinations, inclusive of synchronous and metachronous tumors, and will delve heavily into the CRC pathology to search for features known to exist in classical Lynch syndrome, namely mucoid features in concert with an excess of signet cells and tumor infiltrating lymphocytes, microsatellite instability, and immunohistochemistry. In addition to the specimens and records that we currently have access to, we will intensify our efforts at acquiring slides and tumor blocks for review by our collaborator Zoran Gatalica, M.D., D.Sc., Director of Anatomic Pathology at Creighton. This effort, as well as the mentioned DNA collection and testing, will require a full-time laboratory technician and supplies, who will work under the direction Mary Jansen, R.N., B.S.N., who is coordinating these projects under the direction of Dr. Lynch.
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