A clinically applicable molecular-based classification for endometrial cancers

A. Talhouk, M. K. McConechy, S. Leung, H. H. Li-Chang, J. S. Kwon, N. Melnyk, W. Yang, J. Senz, N. Boyd, Anthony Karnezis, D. G. Huntsman, C. B. Gilks, J. N. McAlpine

Research output: Contribution to journalArticle

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Abstract

Background:Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.Methods:Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.Results:Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.Conclusions:Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Original languageEnglish (US)
Pages (from-to)299-310
Number of pages12
JournalBritish Journal of Cancer
Volume113
Issue number2
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Endometrial Neoplasms
Atlases
Genome
DNA Mismatch Repair
Neoplasms
Immunohistochemistry
Molecular Models
Lymph
Paraffin
Formaldehyde
Blood Vessels
Clinical Trials
Costs and Cost Analysis
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Talhouk, A., McConechy, M. K., Leung, S., Li-Chang, H. H., Kwon, J. S., Melnyk, N., ... McAlpine, J. N. (2015). A clinically applicable molecular-based classification for endometrial cancers. British Journal of Cancer, 113(2), 299-310. https://doi.org/10.1038/bjc.2015.190

A clinically applicable molecular-based classification for endometrial cancers. / Talhouk, A.; McConechy, M. K.; Leung, S.; Li-Chang, H. H.; Kwon, J. S.; Melnyk, N.; Yang, W.; Senz, J.; Boyd, N.; Karnezis, Anthony; Huntsman, D. G.; Gilks, C. B.; McAlpine, J. N.

In: British Journal of Cancer, Vol. 113, No. 2, 01.01.2015, p. 299-310.

Research output: Contribution to journalArticle

Talhouk, A, McConechy, MK, Leung, S, Li-Chang, HH, Kwon, JS, Melnyk, N, Yang, W, Senz, J, Boyd, N, Karnezis, A, Huntsman, DG, Gilks, CB & McAlpine, JN 2015, 'A clinically applicable molecular-based classification for endometrial cancers', British Journal of Cancer, vol. 113, no. 2, pp. 299-310. https://doi.org/10.1038/bjc.2015.190
Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N et al. A clinically applicable molecular-based classification for endometrial cancers. British Journal of Cancer. 2015 Jan 1;113(2):299-310. https://doi.org/10.1038/bjc.2015.190
Talhouk, A. ; McConechy, M. K. ; Leung, S. ; Li-Chang, H. H. ; Kwon, J. S. ; Melnyk, N. ; Yang, W. ; Senz, J. ; Boyd, N. ; Karnezis, Anthony ; Huntsman, D. G. ; Gilks, C. B. ; McAlpine, J. N. / A clinically applicable molecular-based classification for endometrial cancers. In: British Journal of Cancer. 2015 ; Vol. 113, No. 2. pp. 299-310.
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abstract = "Background:Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.Methods:Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.Results:Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.Conclusions:Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.",
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AU - Yang, W.

AU - Senz, J.

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AU - Karnezis, Anthony

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AU - Gilks, C. B.

AU - McAlpine, J. N.

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N2 - Background:Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.Methods:Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.Results:Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.Conclusions:Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

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