Elsevier

Gynecologic Oncology

Volume 116, Issue 3, March 2010, Pages 516-521
Gynecologic Oncology

Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening

https://doi.org/10.1016/j.ygyno.2009.11.021Get rights and content

Abstract

Objective

Lynch syndrome (LS) is characterized by a high lifetime incidence of colorectal cancer and gynecologic malignancies such as endometrial and ovarian cancer. Identification of LS families is important as it allows for heightened cancer screening which decreases colorectal cancer mortality. The original 1996 Bethesda guidelines included two gynecologic populations that should be further evaluated for LS: those with endometrial cancer before the age of 45 years and those with two LS-related cancers (i.e. synchronous endometrial and ovarian cancer). Our study aims to estimate the prevalence of LS in these two populations.

Methods

We utilized a diagnostic algorithm that included immunohistochemistry for mismatch repair protein expression followed by selective evaluation for microsatellite instability and MLH1 gene promoter methylation.

Results

Among 72 eligible patients, 9 (12%) had molecular findings consistent with LS: 6/50 (12%) in the early-onset endometrial cancer group and 3/22 (14%) in the synchronous primary cancer group. In an additional 3 cases, MLH1 silencing was due to promoter methylation: 1/50 (2%) in the early-onset endometrial cancer group and 2/22 (9%) in the synchronous primary cancer group. Of the 9 women with molecular criteria suggesting LS, only three had pedigrees meeting the Amsterdam criteria.

Conclusions

A diagnostic algorithm can identify patients with LS and those who warrant further genetic testing. Our findings reinforce the recommendation that women diagnosed with endometrial cancer before the age of 45 years and women with synchronous endometrial and ovarian cancer be screened for LS, irrespective of family history.

Introduction

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), results from the autosomal dominant inheritance of a mutated DNA mismatch repair (MMR) gene. Clinically, LS families have up to an 80% risk of developing colorectal cancer, a 60% risk of developing endometrial cancer and a 12% risk of developing ovarian cancer [1], [2]. Cancers of the stomach, pancreas, upper urinary tract, biliary tract and small intestine are also reported in LS families [3]. Identification of LS in affected individuals has important implications for screening in individuals as well as family members, as close screening and surveillance has been shown to reduce the mortality of colorectal cancer by over 60% [4].

The initial (1991) and revised (1998) Amsterdam criteria were developed to identify families at high risk for LS [5], [6]. These criteria required colorectal or other LS-associated cancers in three first-degree relatives, occurring in at least two successive generations, and in one individual under the age of 50 years. These criteria were recognized to have poor sensitivity in identifying individuals carrying an LS gene mutation. Therefore, the Bethesda guidelines were introduced to broaden testing recommendations and to identify a greater proportion of affected individuals. The original 1996 Bethesda guidelines recommended molecular testing for LS in six groups of patients, including two gynecologic cancer populations: those with endometrial cancer diagnosed before 45 years of age and those with two LS-related cancers (i.e. synchronous endometrial and ovarian cancers) [7]. The Bethesda guidelines were revised in 2002 to enhance the sensitivity and specificity of the original recommendations, but they failed to specify which gynecologic cancers should undergo further testing [8].

The majority of LS results from an inherited germline mutation in one of three mismatch repair (MMR) genes, MLH1, MSH2, or MSH6[9], [10]. Deficient MMR protein activity leads to DNA microsatellite instability (MSI) and absent immunohistochemical protein expression in tumor tissue [11]. The pattern of abnormal staining provides guidance as to which of the MMR genes is likely to harbor a germline mutation [12]. However, epigenetic silencing of the MLH1 gene by promoter methylation can also result in defective MMR protein activity [13]. This is a somatic and non-heritable event, and does not warrant further evaluation for LS.

This study was designed to utilize a diagnostic algorithm to estimate the prevalence of LS in two gynecologic populations for whom screening is recommended by the 1996 Bethesda guidelines; women less than 45 years of age at diagnosis with endometrial cancer and women with synchronous endometrial and ovarian cancers.

Section snippets

Patient population

After institutional review board approval, 72 patients were identified from a pathology database at Cedars-Sinai Medical Center in Los Angeles, CA. Group 1 included 50 patients with endometrial cancer diagnosed before 45 years of age and group 2 included 22 patients with synchronous endometrial and ovarian cancers (no age restriction). Cases were selected between March 1994 and August 2008 based on the availability of pathologic materials for analysis. During that equivalent time period, there

Results

Patient characteristics are summarized in Table 1. Results of the molecular analysis for group 1 (50 early-onset endometrial cancers) and group 2 (22 synchronous endometrial and ovarian cancers) are detailed in Tables 2 and 3, respectively. Absence of staining for MLH1 or MSH2 was found in 7 (14%) tumors in group 1 and in 5 (23%) tumors in group 2. A strong correlation existed between negative IHC staining and MSI of tumor in both groups.

Those tumors with absent MLH1 immunohistochemistry were

Discussion

Among two populations of gynecologic oncology patients that are recommended to undergo genetic testing by the 1996 Bethesda guidelines, we found 12% (6/50) of the early-onset endometrial cancer group and 14% (3/22) of the synchronous endometrial and ovarian cancer group to have tumors with molecular characteristics suggestive of LS. Only three of these nine patients had a pedigree pattern that met the revised Amsterdam criteria for LS.

Screening by IHC for MMR proteins followed by selective MSI

Conflict of interest statement

There are no financial disclosures from any authors.

This is an original manuscript. Data were presented in abstract form at the Society of Gynecologic Oncologists 40th Annual Meeting on Women's Cancers, San Antonio, TX, on February 9, 2009.

Acknowledgments

Research support provided by the Gynecologic Cancer Foundation/Lee Kaplan Ovarian Cancer Research Grant Award (C.S.W.), the General Clinical Research Center Grant M01-RR00425 (C.S.W.), the American Cancer Society California Division-Early Detection Professorship Grant SIOP-06-258-01-CCE (B.Y.K.), the Women's Cancer Research Institute (C.S.W. and B.Y.K.), and NIH Grant 2 R01 CA026038-30 (H.P.K.).

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