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Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers.

Jumppanen M, Gruvberger-Saal S, Kauraniemi P, Tanner M, Bendahl PO, Lundin M, Krogh M, Kataja P, Borg A, Fernö M, Isola J - Breast Cancer Res. (2007)

Bottom Line: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature.IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers.A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Seinäjoki Central Hospital, Hanneksenrinne 7, FIN-60220 Seinäjoki, Finland. mervi.jumppanen@epshp.fi

ABSTRACT

Introduction: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup.

Methods: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed.

Results: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification.

Conclusion: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors.

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Hierarchical clustering of 50 ER-negative tumors based on the intrinsic gene set [7]. Yellow indicates the basal-like cluster and black the non-basal-like cluster. The black boxes beneath indicate the basal-like cluster by the top 500 basal genes, immunohistochemically CK5/14-positive tumors, and HER-2 amplified tumors (solid box, positive; open box, negative, crossed box, data missing).
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Figure 2: Hierarchical clustering of 50 ER-negative tumors based on the intrinsic gene set [7]. Yellow indicates the basal-like cluster and black the non-basal-like cluster. The black boxes beneath indicate the basal-like cluster by the top 500 basal genes, immunohistochemically CK5/14-positive tumors, and HER-2 amplified tumors (solid box, positive; open box, negative, crossed box, data missing).

Mentions: We next explored how the so-called 'intrinsic' gene set generated by Perou and colleagues [6-8] would perform in our data set. Mapping of their intrinsic gene list [8] to our data with the use of Unigene Cluster ID as an identifier produced a list of 522 clones. These clones were used to cluster the whole data set, which gave expected results separating basal/ER-, luminal/ER+ and ERBB2+/ER- tumor groups from each other similarly to the original study (data not shown) [6,8]. Hierarchical clustering of the ER-negative tumor group separately, with the use of the intrinsic gene set, generated a dendrogram with two major subgroups very similar to the hierarchical clustering analysis with our top 500 ranked basal genes (concordance 90%, p = 0.0001; Figure 2). The basal-like cluster included most of the CK5/14-positive tumors and nine additional CK5/14-negative tumors. The tumors in the non-basal subgroup showed frequent HER-2 amplification (17/27) and predominantly a CK5/14-negative immunophenotype (23/27; Figure 2; see Additional file 3 for the heat map). The basal phenotype classification by Sorlie's intrinsic gene set correlated strongly with basal cytokeratin IHC (concordance 76%, p = 0.0011). Interestingly, seven of the nine misclassified CK5/14-negative tumors by Sorlie's intrinsic gene set were also found to belong to the basal-like cluster when our top 500 CK5/14-associated genes were used in hierarchical clustering analysis.


Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers.

Jumppanen M, Gruvberger-Saal S, Kauraniemi P, Tanner M, Bendahl PO, Lundin M, Krogh M, Kataja P, Borg A, Fernö M, Isola J - Breast Cancer Res. (2007)

Hierarchical clustering of 50 ER-negative tumors based on the intrinsic gene set [7]. Yellow indicates the basal-like cluster and black the non-basal-like cluster. The black boxes beneath indicate the basal-like cluster by the top 500 basal genes, immunohistochemically CK5/14-positive tumors, and HER-2 amplified tumors (solid box, positive; open box, negative, crossed box, data missing).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851391&req=5

Figure 2: Hierarchical clustering of 50 ER-negative tumors based on the intrinsic gene set [7]. Yellow indicates the basal-like cluster and black the non-basal-like cluster. The black boxes beneath indicate the basal-like cluster by the top 500 basal genes, immunohistochemically CK5/14-positive tumors, and HER-2 amplified tumors (solid box, positive; open box, negative, crossed box, data missing).
Mentions: We next explored how the so-called 'intrinsic' gene set generated by Perou and colleagues [6-8] would perform in our data set. Mapping of their intrinsic gene list [8] to our data with the use of Unigene Cluster ID as an identifier produced a list of 522 clones. These clones were used to cluster the whole data set, which gave expected results separating basal/ER-, luminal/ER+ and ERBB2+/ER- tumor groups from each other similarly to the original study (data not shown) [6,8]. Hierarchical clustering of the ER-negative tumor group separately, with the use of the intrinsic gene set, generated a dendrogram with two major subgroups very similar to the hierarchical clustering analysis with our top 500 ranked basal genes (concordance 90%, p = 0.0001; Figure 2). The basal-like cluster included most of the CK5/14-positive tumors and nine additional CK5/14-negative tumors. The tumors in the non-basal subgroup showed frequent HER-2 amplification (17/27) and predominantly a CK5/14-negative immunophenotype (23/27; Figure 2; see Additional file 3 for the heat map). The basal phenotype classification by Sorlie's intrinsic gene set correlated strongly with basal cytokeratin IHC (concordance 76%, p = 0.0011). Interestingly, seven of the nine misclassified CK5/14-negative tumors by Sorlie's intrinsic gene set were also found to belong to the basal-like cluster when our top 500 CK5/14-associated genes were used in hierarchical clustering analysis.

Bottom Line: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature.IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers.A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%).

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Seinäjoki Central Hospital, Hanneksenrinne 7, FIN-60220 Seinäjoki, Finland. mervi.jumppanen@epshp.fi

ABSTRACT

Introduction: Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup.

Methods: IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed.

Results: From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification.

Conclusion: Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors.

Show MeSH
Related in: MedlinePlus