Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation.
OBJECTIVE
The aim of this study was to evaluate number and types of synchronous and metachronous malignancies in patients with endometrial carcinoma with and without microsatellite instability (MSI).


METHODS
From a series of 413 endometrial cancer patients, we identified 94 patients with MSI-positive (MSI+) cancers and grouped them by tumor MLH1 promoter methylation status. These 94 patients were matched by year of surgery to 94 patients with MSI-negative (MSI-) endometrial cancers from the same series. Medical records were reviewed for clinicopathologic information including rates and types of synchronous and metachronous malignancies. Hereditary nonpolyposis colorectal cancer (HNPCC)-associated second and third cancers were analyzed for MSI and MSH2, MSH6, and MLH1 expression for comparison with the corresponding endometrial cancers.


RESULTS
The MSI+ and MSI- cohorts were similar with regard to age, race, grade, and histology. Twenty-eight MSI+ endometrial cancers (29.8%) were MLH1 unmethylated. Rates of synchronous and metachronous cancers were also similar in the MSI+ and MSI- groups at 20 and 23%, respectively. However, patients with MSI+ MLH1 unmethylated endometrial cancers had an excess of HNPCC-associated second and third cancers compared with those with MSI+ MLH1 methylated and MSI- endometrial cancers (18% versus 4.5%, P = 0.034, and 2.1%, P = 0.002). Six of seven second tumors from 5 patients with MSI+ MLH1 unmethylated endometrial cancers showed concordant MSI and mismatch repair protein expression status.


CONCLUSIONS
Our observation that patients with MSI-positive MLH1 unmethylated endometrial carcinoma are at increased risk for HNPCC-associated synchronous and metachronous malignancies suggests inherited cancer susceptibility. These patients and their families may warrant more intense cancer surveillance.
Buttin
Barbara M
BM
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Powell
Matthew A
MA
Mutch
David G
DG
Rader
Janet S
JS
Herzog
Thomas J
TJ
Gibb
Randall K
RK
Huettner
Phyllis
P
Edmonston
Tina Bocker
TB
Goodfellow
Paul J
PJ
D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats; D008875:Middle Aged; D008954:Models, Biological; D016609:Neoplasms, Second Primary / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012306:Risk; D013629:Tamoxifen / Q000627:therapeutic use
D013629:Tamoxifen; D004247:DNA