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Comparative microRNA profiling of sporadic and BRCA1 associated basal-like breast cancers.

Yan M, Shield-Artin K, Byrne D, Deb S, Waddell N, kConFab Investigators, kConFabHaviv I, Fox SB - BMC Cancer (2015)

Bottom Line: This was confirmed in the validation cohort (all p < 0.001).Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomical Pathology, Prince of Wales Hospital, School of Medical Sciences, University of New South Wales, Randwick, 2031, Australia. max.yan@sesiahs.health.nsw.gov.au.

ABSTRACT

Background: While a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use.

Methods: miRNA expression was assessed in 11 BRCA1 basal, 16 sporadic basal, 17 luminal grade 3 cancers via microarrays. The expression of Cyclin D1, FOXP1, FIH-1, pan-ERβ, NRP1 and CD99, predicted to be regulated by BRCA1 specific miRNAs by computer prediction algorithms, was assessed via immunohistochemistry in a cohort of 35 BRCA1 and 52 sporadic basal-like cancers. Assessment of cyclin D1, FOXP1, NRP1 and CD99 expression was repeated on a validation cohort of 82 BRCA1 and 65 sporadic basal-like breast cancers.

Results: Unsupervised clustering of basal cancers resulted in a "sporadic" cluster of 11 cancers, and a "BRCA1" cluster of 16 cancers, including a subgroup composed entirely of 10 BRCA1 cancers. Compared with sporadic basal cancers, BRCA1 cancers showed reduced positivity for proteins predicted to be regulated by miRNAs: FOXP1 (6/20[30 %] vs. 37/49[76 %], p < 0.001), cyclin D1 (8/22[36 %] vs. 30/46[65 %], p = 0.025), NRP1 (2/20[10 %] vs. 23/46[50 %], p = 0.002). This was confirmed in the validation cohort (all p < 0.001). Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.

Conclusion: Sporadic and BRCA1 basal-like cancers have grade independent miRNA expression profiles. Furthermore miRNA driven differences in the expression of proteins in BRCA1 basal cancers may be detected via immunohistochemistry. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.

No MeSH data available.


Related in: MedlinePlus

Three-dimensional PCA plot of gene expression array data for 14 BRCA1 and 10 non-BRCA1 basal cancers
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Fig3: Three-dimensional PCA plot of gene expression array data for 14 BRCA1 and 10 non-BRCA1 basal cancers

Mentions: The subset of predicted target mRNAs in BRCA1 and sporadic basal cancers, differentially expressed due to miRNA and RISC mediated cleavage was then investigated. Gene expression was compared between 14 BRCA1 basal and 10 non-BRCA1 basal cancers derived from Waddell et al.’s cohort. In a three-dimensional plot generated from an exploratory principle component analysis, the BRCA1 cancers formed a small cluster within a larger cluster incorporating all basal cancers (Fig. 3). Genes differentially expressed between BRCA1 and sporadic basal cancers were cross-matched with list of genes predicted to be targeted by differentially expressed miRNAs, to obtain a list of genes predicted to be regulated by RISC mediated cleavage (Additional file 1: Table S6).Fig. 3


Comparative microRNA profiling of sporadic and BRCA1 associated basal-like breast cancers.

Yan M, Shield-Artin K, Byrne D, Deb S, Waddell N, kConFab Investigators, kConFabHaviv I, Fox SB - BMC Cancer (2015)

Three-dimensional PCA plot of gene expression array data for 14 BRCA1 and 10 non-BRCA1 basal cancers
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4494690&req=5

Fig3: Three-dimensional PCA plot of gene expression array data for 14 BRCA1 and 10 non-BRCA1 basal cancers
Mentions: The subset of predicted target mRNAs in BRCA1 and sporadic basal cancers, differentially expressed due to miRNA and RISC mediated cleavage was then investigated. Gene expression was compared between 14 BRCA1 basal and 10 non-BRCA1 basal cancers derived from Waddell et al.’s cohort. In a three-dimensional plot generated from an exploratory principle component analysis, the BRCA1 cancers formed a small cluster within a larger cluster incorporating all basal cancers (Fig. 3). Genes differentially expressed between BRCA1 and sporadic basal cancers were cross-matched with list of genes predicted to be targeted by differentially expressed miRNAs, to obtain a list of genes predicted to be regulated by RISC mediated cleavage (Additional file 1: Table S6).Fig. 3

Bottom Line: This was confirmed in the validation cohort (all p < 0.001).Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomical Pathology, Prince of Wales Hospital, School of Medical Sciences, University of New South Wales, Randwick, 2031, Australia. max.yan@sesiahs.health.nsw.gov.au.

ABSTRACT

Background: While a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use.

Methods: miRNA expression was assessed in 11 BRCA1 basal, 16 sporadic basal, 17 luminal grade 3 cancers via microarrays. The expression of Cyclin D1, FOXP1, FIH-1, pan-ERβ, NRP1 and CD99, predicted to be regulated by BRCA1 specific miRNAs by computer prediction algorithms, was assessed via immunohistochemistry in a cohort of 35 BRCA1 and 52 sporadic basal-like cancers. Assessment of cyclin D1, FOXP1, NRP1 and CD99 expression was repeated on a validation cohort of 82 BRCA1 and 65 sporadic basal-like breast cancers.

Results: Unsupervised clustering of basal cancers resulted in a "sporadic" cluster of 11 cancers, and a "BRCA1" cluster of 16 cancers, including a subgroup composed entirely of 10 BRCA1 cancers. Compared with sporadic basal cancers, BRCA1 cancers showed reduced positivity for proteins predicted to be regulated by miRNAs: FOXP1 (6/20[30 %] vs. 37/49[76 %], p < 0.001), cyclin D1 (8/22[36 %] vs. 30/46[65 %], p = 0.025), NRP1 (2/20[10 %] vs. 23/46[50 %], p = 0.002). This was confirmed in the validation cohort (all p < 0.001). Negative staining for 2 or more out of FOXP1, cyclin D1 and NRP1 predicts germline BRCA1 mutation with a sensitivity of 92 %, specificity of 44 %, positive predictive value of 38 % and a negative predictive value of 94 %.

Conclusion: Sporadic and BRCA1 basal-like cancers have grade independent miRNA expression profiles. Furthermore miRNA driven differences in the expression of proteins in BRCA1 basal cancers may be detected via immunohistochemistry. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient's family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing.

No MeSH data available.


Related in: MedlinePlus