Article

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40 years of age and younger

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States.
Gynecologic Oncology (Impact Factor: 3.77). 07/2011; 123(1):88-94. DOI: 10.1016/j.ygyno.2011.06.005
Source: PubMed

ABSTRACT

The hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to examine risk factors and outcomes in patients 40 years of age and younger with endometrial cancer.
We performed a retrospective cohort study of patients aged 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry was performed. Cases were analyzed according to the presence of DNA MMR protein defects. Standard two-sided statistical tests were performed.
Of the 56 identified patients, the median age was 36 years (range, 24-40). The majority of the endometrial carcinomas were of endometrioid histology (91%), stage I (71%), and FIGO grade 1 (59%). Abnormal DNA MMR was found in 9 cases (16%). Cases with abnormal DNA MMR had lower body mass index (BMI) (P=0.05), and had a family history suggestive of Lynch syndrome (P=0.001). Tumors were more likely to have advanced stage disease (P<0.001), be high grade (P<0.001), have deep myometrial invasion (P<0.001), and have lymphovascular invasion (P=0.002). Cases with abnormal DNA MMR had significantly worse overall survival (P=0.028) and progression-free survival (P=0.042).
Endometrial cancer is rare in women aged 40 years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis.

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    • "suspected or confirmed Lynch II syndrome). The latter group was included in a previous study analyzing the sensitivity of abnormal MMR proteins by IHC showing that abnormal MSH2 on IHC was 94% sensitive for predicting a germline MSH2 deletion [27]. We did not include patients with abnormal MMR IHC for MLH1/PMS2 (loss) as the majority of these cases have MLH1 promoter hypermethylation and represent somatic/ epigenetic inactivation of MLH1 and are unlikely to have a germline mutation in MLH1. "
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    • "Reduced MSH2 protein expression has also been shown to be of unfavorable prognostic value for prostate cancer30, soft tissue sarcoma28, and biliary tract carcinoma11. Unfortunately, in a variety of human cancers, data on the prognosis of down-regulation of MSH2 expression are still contradictory5,12,13,17,19,25. Taking into account HNSCC7, the prognostic value of loss of MSH2 protein expression is unclear, mainly because the few existing studies have presented an insufficient number of patients or perhaps because squamous cell carcinomas from the different anatomic sites of the upper aerodigestive tract seem to exhibit distinct risk factors (environmental and genetic/epigenetic factors), clinical presentations, and outcomes, which may influence the evaluation of potential prognostic markers. "
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    ABSTRACT: This study aimed to investigate the expression of the MSH2 DNA repair protein in head and neck squamous cell carcinoma (HNSCC) in order to analyze its association with clinicopathologic factors and overall survival of patients. Clinical data and primary lesions of HNSSC were collected from 55 patients who underwent surgical resection with postoperative radiotherapy in Montes Claros, state of Minas Gerais, Brazil, between 2000 and 2008. Immunohistochemical reactions were performed to analyze MSH2 protein expression. Bivariate analysis showed no significant correlation or association between MSH2 expression and clinicopathologic parameters by Mann-Whitney and Kruskal-Wallis tests. Patients with locoregional metastatic disease (OR=4.949, p<0.001) and lower MSH2 immunohistochemical expressions (OR=2.943, p=0.032) presented poorer survival for HNSCC by Cox regression models. Our data demonstrated that lower MSH2 expression might contribute to a higher clinic aggressiveness of HNSCC by promoting an unfavorable outcome.
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