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The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer.
Gynecol Oncol. 2006 May; 101(2):238-43.GO

Abstract

OBJECTIVE

Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations.

METHODS

Expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI).

RESULTS

Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLH1 and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype.

CONCLUSIONS

About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer.

Authors+Show Affiliations

Department of Oncology, Institute of Clinical Sciences, Lund University Hospital, SE-221 85 Lund, Sweden. Susanne.Malander@med.lu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16360201

Citation

Malander, Susanne, et al. "The Contribution of the Hereditary Nonpolyposis Colorectal Cancer Syndrome to the Development of Ovarian Cancer." Gynecologic Oncology, vol. 101, no. 2, 2006, pp. 238-43.
Malander S, Rambech E, Kristoffersson U, et al. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol Oncol. 2006;101(2):238-43.
Malander, S., Rambech, E., Kristoffersson, U., Halvarsson, B., Ridderheim, M., Borg, A., & Nilbert, M. (2006). The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecologic Oncology, 101(2), 238-43.
Malander S, et al. The Contribution of the Hereditary Nonpolyposis Colorectal Cancer Syndrome to the Development of Ovarian Cancer. Gynecol Oncol. 2006;101(2):238-43. PubMed PMID: 16360201.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. AU - Malander,Susanne, AU - Rambech,Eva, AU - Kristoffersson,Ulf, AU - Halvarsson,Britta, AU - Ridderheim,Mona, AU - Borg,Ake, AU - Nilbert,Mef, Y1 - 2005/12/19/ PY - 2005/08/31/received PY - 2005/09/30/revised PY - 2005/10/14/accepted PY - 2005/12/20/pubmed PY - 2006/6/13/medline PY - 2005/12/20/entrez SP - 238 EP - 43 JF - Gynecologic oncology JO - Gynecol Oncol VL - 101 IS - 2 N2 - OBJECTIVE: Ovarian cancer has one of the highest fractions of hereditary cases. The hereditary breast and ovarian cancer syndrome, primarily due to mutations in BRCA1 and BRCA2, is the main cause of heredity, but also the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome confers an increased risk of ovarian cancer. In order to clarify the contribution of HNPCC to the development of ovarian cancer, we collected data on family history of cancer and characterized MMR function in a consecutive series of 128 tumors unselected for age at diagnosis and previously characterized for BRCA gene mutations. METHODS: Expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6 was analyzed by immunohistochemistry using tissue microarray sections. Tumors with reduced staining or loss of staining were also analyzed for microsatellite instability (MSI). RESULTS: Loss of MMR protein expression was identified in 3 ovarian cancers, all of which had a MSI-high phenotype. DNA sequence analysis revealed disease-causing germline mutations (deletions of exons 4-6 in MLH1 and a 1-nucleotide deletion in exon 5 of MSH6) in two patients diagnosed at ages 40 and 49 years, both of whom had family histories suggestive of HNPCC. The genetic defect in the third case, which was a 47-year old woman without knowledge about her family history with loss of MLH1/PMS2 expression in the tumor tissue, remains elusive. A family history suggestive of HNPCC was identified in an additional case, but this tumor showed normal, retained MMR protein expression and a microsatellite stable phenotype. CONCLUSIONS: About 2% of ovarian cancer is caused by germline mutations in the MMR-genes, a minor proportion as compared to the contribution of the BRCA-genes (11% in the present series). However, identification of HNPCC patients is important since it allows inclusion of high-risk individuals into control programs aimed at preventing the more frequent colorectal and endometrial cancers. Tumors within the HNPCC-spectrum should therefore be included when recording a family history of cancer among patients diagnosed with ovarian cancer. SN - 0090-8258 UR - https://www.unboundmedicine.com/medline/citation/16360201/The_contribution_of_the_hereditary_nonpolyposis_colorectal_cancer_syndrome_to_the_development_of_ovarian_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(05)00900-5 DB - PRIME DP - Unbound Medicine ER -