Clinical–Alimentary TractThe Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations
Section snippets
Patients and Methods
We tested 99 probands who had an LS-associated tumor (91 colorectal, 5 endometrial, 1 transitional cell of the renal pelvis, 1 small intestinal, and 1 gastric) that demonstrated isolated absence of PMS2 protein on IHC. Of these, 55 were enrolled in research studies approved by the Institutional Review Board at The Ohio State University, which allowed for PMS2 gene testing in our research laboratory. The remaining 44 samples were received anonymously through research collaborations with
Results
Of the 99 probands tested for PMS2 mutations using sequencing and MLPA, 61 (62%) were found to have deleterious mutations in the PMS2 gene. Another 10 probands had missense variants for which the significance has yet to be determined (Figure 1 shows the distribution of identified mutations). In all, 34 different deleterious PMS2 mutations were identified, 11 of which were seen in more than one proband. Five mutations occurred more than twice. The most notable of the 5 exceptions was an
Discussion
This is the largest series of PMS2 mutation carriers reported to date, and probands were identified both by population-based screening of colorectal and/or endometrial tumors and through ascertainment in high-risk specialty clinics. This study illustrates that PMS2 gene mutations account for many cases of LS and perhaps have historically been overlooked and underestimated given the technical difficulty of identifying them. In a previous population-based study of colorectal and endometrial
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Supported by the National Cancer Institute, National Institutes of Health grants CA67941, CA16058, and RFA CA-95-011 and through cooperative agreements with the following: Australasian Colorectal Cancer Family Registry (U01 CA097735); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800); Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Seattle Colorectal Cancer Family Registry (U01 CA074794); grant 04-0570 from the Swedish Cancer Society; grant 06-1252 from The Stockholm Cancer Center Foundation; and The National Health and Medical Research Council, Australia.
The work on samples from the Colon Cancer Family Registries was completed through cooperative agreements with the Ontario Familial Colorectal Cancer Registry, Australasian Colorectal Cancer Family Registry, Mayo Colorectal Cancer Registry, and the Seattle Familial Colorectal Cancer Family Registry.
Conflicts of Interest: No conflicts of interest exist.