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

D D Buchanan; Y Y Tan; M D Walsh; M Clendenning; A M Metcalf; K Ferguson; S T Arnold; B A Thompson; Felicity Lose; M T Parsons; R J Walters; S A Pearson; M Cummings; M K Oehler; P B Blomfield; M A Quinn; J A Kirk; C J Stewart; A Obermair; J P Young; P M Webb; A B Spurdle

doi:10.1200/JCO.2013.51.2129

Back

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 article

Peer reviewed

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

D D Buchanan, Y Y Tan, M D Walsh, M Clendenning, A M Metcalf, K Ferguson, S T Arnold, B A Thompson, Felicity Lose, M T Parsons, …

Journal of Clinical Oncology, Vol.32(2), pp.90-100

2014

DOI: https://doi.org/10.1200/JCO.2013.51.2129

Files and links (1)

url

https://doi.org/10.1200/JCO.2013.51.2129View

Published Version

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. © 2013 by American Society of Clinical Oncology.

Details

Title: 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
Authors: D D Buchanan (Author) - Queensland Institute of Medical Research
Y Y Tan (Author) - University of Queensland
M D Walsh (Author) - Queensland Institute of Medical Research
M Clendenning (Author) - Queensland Institute of Medical Research
A M Metcalf (Author) - Queensland Institute of Medical Research
K Ferguson (Author) - Queensland Institute of Medical Research
S T Arnold (Author) - Queensland Institute of Medical Research
B A Thompson (Author) - Queensland Institute of Medical Research
Felicity Lose (Author) - Queensland Institute of Medical Research
M T Parsons (Author) - Queensland Institute of Medical Research
R J Walters (Author) - Queensland Institute of Medical Research
S A Pearson (Author) - Queensland Institute of Medical Research
M Cummings (Author) - University of Queensland
M K Oehler (Author) - Royal Adelaide Hospital
P B Blomfield (Author) - Royal Hobart Hospital
M A Quinn (Author) - Royal Women's Hospital
J A Kirk (Author) - University of Sydney
C J Stewart (Author) - King Edward Memorial Hospital
A Obermair (Author) - University of Queensland
J P Young (Author) - Queensland Institute of Medical Research
P M Webb (Author) - Queensland Institute of Medical Research
A B Spurdle (Author) - Queensland Institute of Medical Research
Publication details: Journal of Clinical Oncology, Vol.32(2), pp.90-100
Publisher: American Society of Clinical Oncology
Date published: 2014
DOI: 10.1200/JCO.2013.51.2129
ISSN: 0732-183X
Organisation Unit: University of the Sunshine Coast, Queensland; Office of Research
Language: English
Record Identifier: 99450472902621
Output Type: Journal article

Metrics

305 Record Views

181 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Web Of Science research areas: Oncology

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites