Prevalence of Loss of Expression of DNA Mismatch Repair Proteins in Primary Epithelial Ovarian Tumors

Although different histologic subtypes of epithelial ovarian tumors have long been recognized, their molecular abnormalities have not been fully defined. We examined the prevalence of DNA mismatch repair (MMR) protein loss in these tumors. Tissue microarrays (TMA) of suspected ovarian carcinomas were stained for hMLH1, hMSH2, hMSH6, and hPMS2 and scored separately by 2 groups of investigators. Loss of staining (negative) or discrepant staining results on TMA were verified on whole-section slides. Intact (positive) staining results were also verified for an additional 25 randomly selected cases. Clinical data for cases demonstrating MMR protein loss were collected. A second set of TMA composed purely of mucinous tumors was also stained for antibodies to MMR proteins and scored by 1 group of investigators. TMA was an effective method for screening a large number of ovarian tumors for MMR protein expression, with a sensitivity of 100% for all 4 MMR proteins, and a specificity of 22.2%–53.8% for different MMR proteins. Of the primary epithelial tumors of the ovary, loss of expression of MMR proteins was significantly more common in the endometriosis-associated carcinomas (7/69; 10.1%) than in high-grade serous carcinomas (2/182; 1.1%): P=0.0021. The former group also showed more frequent loss of MMR proteins compared with mucinous intestinal-type carcinomas (0/32; P=0.0940). Cases within the group of endometriosis-associated carcinomas were endometrioid (2/29 cases), clear cell (1/27 cases), undifferentiated (1/8 cases), and mixed carcinomas with an endometrioid, clear cell, and/or undifferentiated component (3/5 cases). No loss of MMR protein expression was identified in epithelial tumors of other histologic subtypes. Our study demonstrated the loss of MMR protein expression in 10.1% of endometriosis-associated ovarian carcinomas. These results raise the possibility of selective screening for Lynch syndrome in patients with these types of ovarian carcinoma.

[1]  B. Clarke,et al.  Comparison of clinical schemas and morphologic features in predicting Lynch syndrome in mutation‐positive patients with endometrial cancer encountered in the context of familial gastrointestinal cancer registries , 2012, Cancer.

[2]  S. Bulun,et al.  Endometriosis and Ovarian Cancer: A Review of Clinical, Pathologic, and Molecular Aspects , 2011, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[3]  J. Blaakaer,et al.  The association between endometriosis and gynecological cancers and breast cancer: a review of epidemiological data. , 2011, Gynecologic oncology.

[4]  Matej Horvat,et al.  Microsatellite instability in colorectal cancer , 2011, Radiology and oncology.

[5]  Payal Sipahimalani,et al.  A Histology-Based Model for Predicting Microsatellite Instability in Colorectal Cancers , 2010, The American journal of surgical pathology.

[6]  E. Dogliotti,et al.  Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. , 2010, European journal of cancer.

[7]  L. Tafe,et al.  Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms , 2010, Modern Pathology.

[8]  C. Sempoux,et al.  High risk for neoplastic transformation of endometriosis in a carrier of lynch syndrome , 2010, Familial Cancer.

[9]  R. Barakat,et al.  Endometrial Carcinomas in Women Aged 40 Years and Younger: Tumors Associated With Loss of DNA Mismatch Repair Proteins Comprise a Distinct Clinicopathologic Subset , 2009, The American journal of surgical pathology.

[10]  K. Kosarin,et al.  Selection of Endometrial Carcinomas for DNA Mismatch Repair Protein Immunohistochemistry Using Patient Age and Tumor Morphology Enhances Detection of Mismatch Repair Abnormalities , 2009, The American journal of surgical pathology.

[11]  E. Oliva,et al.  Gynecologic Pathology: A Volume in the Series: Foundations in Diagnostic Pathology , 2009 .

[12]  I. Bernstein,et al.  Risk of gynecologic cancers in Danish hereditary non‐polyposis colorectal cancer families , 2008, Acta obstetricia et gynecologica Scandinavica.

[13]  K. Jensen,et al.  Microsatellite Instability and Mismatch Repair Protein Defects in Ovarian Epithelial Neoplasms in Patients 50 Years of Age and Younger , 2008, The American journal of surgical pathology.

[14]  J. Shia.  Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. , 2008, The Journal of molecular diagnostics : JMD.

[15]  Hiroyuki Yamamoto,et al.  Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. , 2008, Carcinogenesis.

[16]  D. Rosen,et al.  Loss of DNA mismatch repair protein hMSH6 in ovarian cancer is histotype-specific. , 2008, International journal of clinical and experimental pathology.

[17]  B. Karlan,et al.  Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. , 2007, Gynecologic oncology.

[18]  A. Måsbäck,et al.  Ovarian cancer at young age: the contribution of mismatch‐repair defects in a population‐based series of epithelial ovarian cancer before age 40 , 2007, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[19]  John D Potter,et al.  Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. , 2007, Gastroenterology.

[20]  J. Shia,et al.  Utility of Immunohistochemistry in Predicting Microsatellite Instability in Endometrial Carcinoma , 2007, The American journal of surgical pathology.

[21]  D. Rosen,et al.  Immunohistochemical staining of hMLH1 and hMSH2 reflects microsatellite instability status in ovarian carcinoma , 2006, Modern Pathology.

[22]  Harry Campbell,et al.  Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. , 2006, The New England journal of medicine.

[23]  Å. Borg,et al.  The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. , 2006, Gynecologic oncology.

[24]  H. Hollema,et al.  Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer , 2006, Gut.

[25]  D. Bodurka,et al.  Association of Low-Grade Endometrioid Carcinoma of the Uterus and Ovary With Undifferentiated Carcinoma: A New Type of Dedifferentiated Carcinoma? , 2006, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[26]  A. Krasinskas,et al.  Performance of the revised Bethesda guidelines for identification of colorectal carcinomas with a high level of microsatellite instability. , 2005, Archives of pathology & laboratory medicine.

[27]  M. Andreu,et al.  Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. , 2005, JAMA.

[28]  W. Gerald,et al.  Value of Immunohistochemical Detection of DNA Mismatch Repair Proteins in Predicting Germline Mutation in Hereditary Colorectal Neoplasms , 2005, The American journal of surgical pathology.

[29]  R. Broaddus,et al.  Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma. , 2004, Human pathology.

[30]  H. Morreau,et al.  Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. , 2003, The American journal of pathology.

[31]  A. Jakubowska,et al.  Ovarian cancer of endometrioid type as part of the MSH6 gene mutation phenotype , 2002, Journal of Human Genetics.

[32]  P. Parfrey,et al.  Impact of Gender and Parent of Origin on the Phenotypic Expression of Hereditary Nonpolyposis Colorectal Cancer in a Large Newfoundland Kindred With a Common MSH2 Mutation , 2002, Diseases of the colon and rectum.

[33]  P. Møller,et al.  MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Mecklin,et al.  The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. , 2001, Gynecologic oncology.

[35]  N. Maggiano,et al.  hMSH2 and GTBP expression in advanced stage epithelial ovarian cancer , 1999, British Journal of Cancer.

[36]  L. Aaltonen,et al.  Cancer risk in mutation carriers of DNA‐mismatch‐repair genes , 1999, International journal of cancer.

[37]  N. Claij,et al.  Microsatellite instability in human cancer: a prognostic marker for chemotherapy? , 1999, Experimental cell research.

[38]  T. Rebbeck,et al.  BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. , 1998, American journal of obstetrics and gynecology.

[39]  S. Aebi,et al.  The role of DNA mismatch repair in platinum drug resistance. , 1996, Cancer research.

[40]  C. Boland,et al.  Loss of DNA mismatch repair in acquired resistance to cisplatin. , 1996, Cancer research.

[41]  J. Dungan.  Testing Women With Endometrial Cancer to Detect Lynch Syndrome , 2012 .

[42]  C. Tops,et al.  Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? , 2004, Familial Cancer.