The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

doi:10.1053/j.gastro.2008.04.026

Gastroenterology

Volume 135, Issue 2, August 2008, Pages 419-428.e1

https://doi.org/10.1053/j.gastro.2008.04.026 Get rights and content

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.

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.

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Clinical–Alimentary TractThe Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

Section snippets

Patients and Methods

Results

Discussion

Gastroenterology

Gastroenterology

Clin Gastroenterol Hepatol

Genomics

Genomics

Am J Hum Genet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Cell

J Gastrointest Surg

Clin Gastroenterol Hepatol

Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)

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J Clin Oncol

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J Med Genet

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Cancer Res

Long-range PCR facilitates the identification of PMS2-specific mutations

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Getting rid of the PMS2 pseudogenes: mission impossible?

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Extensive gene conversion at the PMS2 DNA mismatch repair locus

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Response to: getting rid of the PMS2 pseudogenes: mission impossible?

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Clinical–Alimentary Tract
The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations