Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Ashley S. Case, Israel Zighelboim, David G. Mutch, Sheri A. Babb, Amy P. Schmidt, Alison J. Whelan, Stephen N Thibodeau, Paul J. Goodfellow

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Objectives: We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. Methods: A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. Results: Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. Conclusions: We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

Original languageEnglish (US)
Pages (from-to)438-444
Number of pages7
JournalGynecologic Oncology
Volume108
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Cluster Analysis
Neoplasms
Microsatellite Instability
Methylation
Carcinoma
Adenomatous Polyps
Pedigree
Genetic Markers
Colonic Neoplasms
Medical Records
Colon
Leukocytes
History
Gene Expression

Keywords

  • DNA mismatch repair
  • Endometrial cancer
  • HNPCC
  • Lynch syndrome

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Case, A. S., Zighelboim, I., Mutch, D. G., Babb, S. A., Schmidt, A. P., Whelan, A. J., ... Goodfellow, P. J. (2008). Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. Gynecologic Oncology, 108(2), 438-444. https://doi.org/10.1016/j.ygyno.2007.09.036

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. / Case, Ashley S.; Zighelboim, Israel; Mutch, David G.; Babb, Sheri A.; Schmidt, Amy P.; Whelan, Alison J.; Thibodeau, Stephen N; Goodfellow, Paul J.

In: Gynecologic Oncology, Vol. 108, No. 2, 02.2008, p. 438-444.

Research output: Contribution to journalArticle

Case, AS, Zighelboim, I, Mutch, DG, Babb, SA, Schmidt, AP, Whelan, AJ, Thibodeau, SN & Goodfellow, PJ 2008, 'Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair', Gynecologic Oncology, vol. 108, no. 2, pp. 438-444. https://doi.org/10.1016/j.ygyno.2007.09.036
Case, Ashley S. ; Zighelboim, Israel ; Mutch, David G. ; Babb, Sheri A. ; Schmidt, Amy P. ; Whelan, Alison J. ; Thibodeau, Stephen N ; Goodfellow, Paul J. / Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. In: Gynecologic Oncology. 2008 ; Vol. 108, No. 2. pp. 438-444.
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abstract = "Objectives: We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. Methods: A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. Results: Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. Conclusions: We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.",
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AU - Case, Ashley S.

AU - Zighelboim, Israel

AU - Mutch, David G.

AU - Babb, Sheri A.

AU - Schmidt, Amy P.

AU - Whelan, Alison J.

AU - Thibodeau, Stephen N

AU - Goodfellow, Paul J.

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N2 - Objectives: We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. Methods: A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. Results: Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. Conclusions: We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

AB - Objectives: We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. Methods: A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. Results: Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. Conclusions: We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

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KW - Endometrial cancer

KW - HNPCC

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