The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.
OBJECTIVE
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.
Senter
Leigha
L
Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
Clendenning
Mark
M
Sotamaa
Kaisa
K
Hampel
Heather
H
Green
Jane
J
Potter
John D
JD
Lindblom
Annika
A
Lagerstedt
Kristina
K
Thibodeau
Stephen N
SN
Lindor
Noralane M
NM
Young
Joanne
J
Winship
Ingrid
I
Dowty
James G
JG
White
Darren M
DM
Hopper
John L
JL
Baglietto
Laura
L
Jenkins
Mark A
MA
de la Chapelle
Albert
A
D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics*; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D022521:Ligase Chain Reaction; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D016017:Odds Ratio; D019683:Penetrance; D010641:Phenotype; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018570:Risk Assessment
D004268:DNA-Binding Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes