Tags

Type your tag names separated by a space and hit enter

Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.
J Clin Oncol. 2014 Jan 10; 32(2):90-100.JC

Abstract

PURPOSE

Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.

PATIENTS AND METHODS

Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).

RESULTS

Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.

CONCLUSION

Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

Authors+Show Affiliations

Daniel D. Buchanan, Yen Y. Tan, Michael D. Walsh, Mark Clendenning, Alexander M. Metcalf, Kaltin Ferguson, Sven T. Arnold, Bryony A. Thompson, Felicity A. Lose, Michael T. Parsons, Rhiannon J. Walters, Sally-Ann Pearson, Joanne P. Young, Penelope M. Webb, and Amanda B. Spurdle, QIMR Berghofer Medical Research Institute, Herston; Yen Y. Tan and Andreas Obermair, University of Queensland School of Medicine, Brisbane; Margaret Cummings, University of Queensland Centre for Clinical Research, Herston, Queensland; Martin K. Oehler, Royal Adelaide Hospital, Adelaide, South Australia; Michael A. Quinn, Royal Women's Hospital, Melbourne, Victoria; Judy A. Kirk, Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales; Colin J. Stewart, King Edward Memorial Hospital, Perth, Western Australia, Australia; and Penelope B. Blomfield, Royal Hobart Hospital, Hobart, Tasmania.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24323032

Citation

Buchanan, Daniel D., et al. "Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-level Germline Mismatch Repair Gene Mutation Testing." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 32, no. 2, 2014, pp. 90-100.
Buchanan DD, Tan YY, Walsh MD, et al. Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. J Clin Oncol. 2014;32(2):90-100.
Buchanan, D. D., Tan, Y. Y., Walsh, M. D., Clendenning, M., Metcalf, A. M., Ferguson, K., Arnold, S. T., Thompson, B. A., Lose, F. A., Parsons, M. T., Walters, R. J., Pearson, S. A., Cummings, M., Oehler, M. K., Blomfield, P. B., Quinn, M. A., Kirk, J. A., Stewart, C. J., Obermair, A., ... Spurdle, A. B. (2014). Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 32(2), 90-100. https://doi.org/10.1200/JCO.2013.51.2129
Buchanan DD, et al. Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-level Germline Mismatch Repair Gene Mutation Testing. J Clin Oncol. 2014 Jan 10;32(2):90-100. PubMed PMID: 24323032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. AU - Buchanan,Daniel D, AU - Tan,Yen Y, AU - Walsh,Michael D, AU - Clendenning,Mark, AU - Metcalf,Alexander M, AU - Ferguson,Kaltin, AU - Arnold,Sven T, AU - Thompson,Bryony A, AU - Lose,Felicity A, AU - Parsons,Michael T, AU - Walters,Rhiannon J, AU - Pearson,Sally-Ann, AU - Cummings,Margaret, AU - Oehler,Martin K, AU - Blomfield,Penelope B, AU - Quinn,Michael A, AU - Kirk,Judy A, AU - Stewart,Colin J, AU - Obermair,Andreas, AU - Young,Joanne P, AU - Webb,Penelope M, AU - Spurdle,Amanda B, Y1 - 2013/12/09/ PY - 2013/12/11/entrez PY - 2013/12/11/pubmed PY - 2014/3/4/medline SP - 90 EP - 100 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J Clin Oncol VL - 32 IS - 2 N2 - PURPOSE: Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations. PATIENTS AND METHODS: Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS). RESULTS: Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered. CONCLUSION: Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation. SN - 1527-7755 UR - https://www.unboundmedicine.com/medline/citation/24323032/Tumor_mismatch_repair_immunohistochemistry_and_DNA_MLH1_methylation_testing_of_patients_with_endometrial_cancer_diagnosed_at_age_younger_than_60_years_optimizes_triage_for_population_level_germline_mismatch_repair_gene_mutation_testing_ L2 - https://ascopubs.org/doi/10.1200/JCO.2013.51.2129?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -