TY - JOUR
T1 - The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations
AU - Senter, Leigha
AU - Clendenning, Mark
AU - Sotamaa, Kaisa
AU - Hampel, Heather
AU - Green, Jane
AU - Potter, John D.
AU - Lindblom, Annika
AU - Lagerstedt, Kristina
AU - Thibodeau, Stephen N.
AU - Lindor, Noralane M.
AU - Young, Joanne
AU - Winship, Ingrid
AU - Dowty, James G.
AU - White, Darren M.
AU - Hopper, John L.
AU - Baglietto, Laura
AU - Jenkins, Mark A.
AU - de la Chapelle, Albert
N1 - Funding Information:
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.
PY - 2008/8
Y1 - 2008/8
N2 - Background & Aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.
AB - Background & Aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.
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U2 - 10.1053/j.gastro.2008.04.026
DO - 10.1053/j.gastro.2008.04.026
M3 - Article
C2 - 18602922
AN - SCOPUS:48549099663
SN - 0016-5085
VL - 135
SP - 419-428.e1
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -