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Uterine cancer is the most common gynecologic malignancy in the United States, with an estimated 63,230 new cases and 11,350 deaths from the disease every year.1 Based on the data from its national cancer database, and Surveillance, Epidemiology and End Results (SEER), the lifetime risk of endometrial cancer is 2.8% and the average age at diagnosis is 62.2 As opposed to ovarian malignancies, the majority of the cases are diagnosed at an early stage (67% at stage I), as more than 90% of women with uterine cancer have an early presenting symptom (abnormal uterine bleeding).3 The most common histologic subtype is adenocarcinoma of the endometrium, which is subcategorized into two distinct groups that differ in incidence, response to therapy and prognosis.4 Type I tumors (80% of endometrial carcinomas), have more favorable outcomes due to grade 1 or 2 endometrioid histology, early stage at diagnosis, retention of hormone receptor status and younger age at onset. On the other hand, type II tumors (20% of endometrial cancers) portend a poorer prognosis, as these represent grade 3 endometrioid tumors and tumors of non-endometrioid histology such as serous, clear cell, mucinous, squamous, transitional cell, mesonephric and undifferentiated. They often lack hormone receptors and there is no clear association with estrogen stimulation.

Hereditary cancer syndromes such as Lynch and Cowden are associated with increased risk of type I malignancies.4 Lynch accounts for 2 to 5% of all endometrial carcinomas,5,6 whereas Cowden syndrome is reported to be even rarer.7


Lynch Syndrome

Lynch syndrome (LS) is a highly penetrant autosomal dominant inherited cancer syndrome, which is characterized by germline mutations in DNA mismatch repair genes (MLH1-chromosome 3p.22, MSH2-chromosome 2p21, MSH6-chromosome 2p16.3, PMS2-chromosome 7p22.1) or deletions in the EPCAM gene (chromosome 2p21). The mismatch repair system maintains genomic integrity by recognizing base-pair mismatches during DNA replication, which most commonly occur at microsatellites (certain DNA motifs that are typically repeated 5 to 50 times). In the setting of a defective mismatch repair system, the microsatellites become more susceptible to mutations leading to expansion or contraction of these regions. This phenomenon is called microsatellite instability, which is a characteristic feature of tumors related to LS.8

The pathogenicity of the disease is described by a two-hit hypothesis, meaning that patients inherit one defective allele, which is followed by inactivation of the second allele via either somatic mutation, loss of heterozygosity or non-inherited methylation of the MLH1 promoter (epigenetic silencing). Among the four mismatch repair genes, the most common mutation is seen in MSH2 (41%), followed by MLH1 (31%), MSH6 (13%) and PMS2 (9%).9,10 Pathogenic mutations in PMS2 have a lower penetrance than the mutations in the other three genes. Deletions in EPCAM genes lead to silencing of neighboring MSH2 via transcriptional read-through, which is the ...

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