University of Louisville
A Microgenomic Approach to Identify Clinically Relevant Gene Signatures that Discriminate Between Invasive Lobular and Ductal Breast Carcinomas
Institution
University of Louisville
Faculty Advisor/ Mentor
James L. Wittliff
Abstract
In an effort to distinguish between the two most common invasive breast carcinomas, lobular (ILC) and ductal (IDC), we searched for a genomic marker that discriminates these histologic types when conventional tests are conflicting. A specific genomic marker would be useful to distinguish IDC from ILC, due to the varied responses of luminal A-like-IDC and ILC to the aromatase inhibitor letrozole in post-menopausal women [Metzger et al. Cancer Res 2012]. Although CGH analysis shows that ILC is closely related to low grade IDC (luminal A-like) and genetically unrelated to intermediate and high grade IDC [Pathol Res Pract 2005; 201:713], ILC response to letrozole is more like luminal-B-like IDC (intermediate or high grade). To identify candidate genes, microarray analysis of expression levels were evaluated in laser capture microdissected carcinoma cells of biopsies that were positive for estrogen (ER) and progesterone receptors (PR). In low grade IDC and ILC, 299 probes were differentially expressed (p<0.01), and 99 of these probes were not differentially expressed (p>0.01) between high grade IDC and ILC. These 99 genes serve as candidates for a genomic marker differentiating these two histologic types. Microarray results showed varying expression levels of BRWD1, CAPSL, CHRNA, CMTM7, CRMP1, GSKIP, HBEGF, PAPPA, and LRBA among the different cancer pathologies. By using quantitative polymerase chain reaction (qPCR), we determined expression levels relative to Actin, beta for the gene candidates in order to validate those from the microarray array results. qPCR analyses are used to validate and refine the gene subset distinguishing ILC from low grade IDC. Our novel approach is revealing microgenomic features that discriminate these carcinomas which exhibit different clinical behaviors. Supported in part by a grant from NIH/NCI R25-CA134283 and Phi Beta Psi Charity Trust.
A Microgenomic Approach to Identify Clinically Relevant Gene Signatures that Discriminate Between Invasive Lobular and Ductal Breast Carcinomas
In an effort to distinguish between the two most common invasive breast carcinomas, lobular (ILC) and ductal (IDC), we searched for a genomic marker that discriminates these histologic types when conventional tests are conflicting. A specific genomic marker would be useful to distinguish IDC from ILC, due to the varied responses of luminal A-like-IDC and ILC to the aromatase inhibitor letrozole in post-menopausal women [Metzger et al. Cancer Res 2012]. Although CGH analysis shows that ILC is closely related to low grade IDC (luminal A-like) and genetically unrelated to intermediate and high grade IDC [Pathol Res Pract 2005; 201:713], ILC response to letrozole is more like luminal-B-like IDC (intermediate or high grade). To identify candidate genes, microarray analysis of expression levels were evaluated in laser capture microdissected carcinoma cells of biopsies that were positive for estrogen (ER) and progesterone receptors (PR). In low grade IDC and ILC, 299 probes were differentially expressed (p<0.01), and 99 of these probes were not differentially expressed (p>0.01) between high grade IDC and ILC. These 99 genes serve as candidates for a genomic marker differentiating these two histologic types. Microarray results showed varying expression levels of BRWD1, CAPSL, CHRNA, CMTM7, CRMP1, GSKIP, HBEGF, PAPPA, and LRBA among the different cancer pathologies. By using quantitative polymerase chain reaction (qPCR), we determined expression levels relative to Actin, beta for the gene candidates in order to validate those from the microarray array results. qPCR analyses are used to validate and refine the gene subset distinguishing ILC from low grade IDC. Our novel approach is revealing microgenomic features that discriminate these carcinomas which exhibit different clinical behaviors. Supported in part by a grant from NIH/NCI R25-CA134283 and Phi Beta Psi Charity Trust.