Elsevier

Human Pathology

Volume 36, Issue 12, December 2005, Pages 1322-1326
Human Pathology

Case report
Breast cancer in an MSH2 gene mutation carrier

https://doi.org/10.1016/j.humpath.2005.08.025Get rights and content

Summary

A 49-year-old woman presented with breast cancer. She is a member of a family with the hereditary nonpolyposis colorectal cancer syndrome for which a 2–base pair deletion in exon 11 of the mismatch repair gene MSH2 (c1705_1706 delGA) had been identified. Breast cancer is rare in the hereditary nonpolyposis colorectal cancer syndrome. Microsatellite analysis of the tumor showed a microsatellite instable pattern for markers Bat25, Bat26, and Bat40, and no changes for markers D2S123 and D5S346, a so-called microsatellite instability–high pattern. Immunohistochemical staining for the mismatch repair enzymes MSH2 and MSH6 was negative, whereas the tumor cells were positive for MLH1, a pattern suggestive for biallelic MSH2 gene inactivation. We tested the tumor for loss of heterozygosity of the MSH2 gene and found loss of the wild-type MSH2 allele. These data strongly suggest that the MSH2 gene was involved in the development of this breast tumor.

Introduction

The MSH2 gene is coding for one of the mismatch repair enzymes involved in the repair of DNA replication errors. Microsatellites, tandem repeats of 1 to 5 base pairs (bp), are extremely vulnerable for replication errors. As a result, microsatellite instability (MSI) is a hallmark of defective DNA repair. Replication errors in microsatellites will result in an increase or decrease in the length of the tandem repeats that can be detected after DNA amplification. Germline mutations in the MSH2 gene are associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. This syndrome is also associated with mutations in other mismatch repair genes, MLH1, MSH6, PMS2, and rarely PMS1. Carriers of mutations in these mismatch repair genes are at an increased risk for developing colorectal cancer, but also a number of extracolonic cancers. Of these latter, cancer of the endometrium, small bowel, ureter, and pelvis has been included in the clinical criteria for recognition of the HNPCC syndrome [1]. Breast cancer is not included in these clinical criteria, and no increased lifetime risk was reported [1]. We report here a case of breast cancer in an MSH2 gene mutation carrier in which we were able to demonstrate that this mutation was involved in the development of this tumor by loss of the wild-type MSH2 allele.

Section snippets

Case report

A 49-year-old woman reported with a palpable lesion in her right breast. Mammography revealed a density in her right breast, which was thought to be malignant (BI-RAD 5). A carcinoma was diagnosed in a core needle biopsy. A lumpectomy with sentinel lymph node procedure was performed. On histological examination, a 2.1-cm-wide invasive ductal carcinoma, Bloom and Richardson grade 2 with positive staining for estrogen and progesterone receptor, was found. The tumor was remarkable for the presence

Results

The tumor cells showed strong cytoplasmic expression of cytokeratin 8/18 (Fig. 1).

Immunohistochemistry for mismatch repair protein expression demonstrated absence of expression of MSH2 and MSH6 in the tumor cell nuclei, whereas normal cells showed nuclear expression of these proteins. MLH1 and PMS2 were expressed both in nuclei of the tumor cells and normal cells (Fig. 1).

The MSI analysis revealed unequivocally an MSI pattern for the mononucleotide repeat markers Bat25, Bat26, and Bat40.

Discussion

Breast cancer is not included in the clinical criteria for the recognition of patients with the HNPCC syndrome [1]. The MSI phenotype is rare in unselected breast cancers [2]. In a study of MSI in patients that presented with synchronous or metachronous breast and colorectal cancer, no MSI was found in the breast cancers [3]. Breast cancer with an MSI-high pattern has been reported in the Dutch HNPCC register [4], [5]. In this register, breast cancer was found in 5 patients with MLH1 germline

References (15)

There are more references available in the full text version of this article.

Cited by (33)

  • Prognostic significance of hMSH2, hMSH3, and hMSH6 expression in ameloblastoma

    2017, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
    Citation Excerpt :

    To avoid the accumulation of genetic mutations, humans possess a complex group of proteins that form the MMR system, which is responsible for identifying and correcting errors in the pairing process of nucleotide bases during DNA replication.12,16 Here, we investigated the importance of hMutS proteins for ameloblastoma pathogenesis and behavior.14,18-24 Our results demonstrated that hMSH2 and hMSH3 expression is associated with BRAF-V600E mutation and that simultaneous overexpression of hMSH2, hMSH3, and hMSH6 is associated with increased likelihood of recurrence, although the proteins did not predict the DFS rates of these patients.

  • Application of molecular findings to the diagnosis and management of breast disease: Recent advances and challenges

    2011, Human Pathology
    Citation Excerpt :

    Sporadic breast cancers showing the same histopathological and immunohistochemical features also show evidence of down-regulated or dysfunctional BRCA1, for example, by BRCA1 gene methylation or overexpression of inhibitor of DNA binding 4, a negative regulator of BRCA1 [116,119-121]. Interestingly, triple-negative breast cancers, with medullary-like morphology and dense lymphocytic infiltrate, are also overrepresented in sporadic and hereditary (Lynch syndrome) breast cancers associated with MSI/MMR deficiency [100,122-124]. Patients with triple-negative breast cancers, whether sporadic or inherited, are faced with an aggressive tumor for which there is currently no targeted treatment option available.

  • Lynch syndrome and gynaecologic's cancer: follow-up recommendations

    2007, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
View all citing articles on Scopus
View full text