Abstract B3: Genomic characterization of triple-negative breast cancers with high-resolution SNP 6.0 Affymetrix arrays
Authors: Emanuele de Rinaldis, Anita Grigoriadis, Mamunur Rashid, Patrycja Gazinska, Leticia Bosshard-Carter, Elodie Noel, Cheryl Gillett, Pierfrancesco Marra, Andrew Tutt
Journal: Clinical Cancer Research (2010)

Abstract Introduction: The histopathological absence of ER, PR, and HER2 defines a subgroup of breast cancers named triple negative, characterized by aggressive behavior and poor prognosis. These tumors represent a significant clinical challenge as little is known about the genetic alterations underlying their development and, as a consequence, no specific targeted therapies are yet available. Using high-resolution SNP6.0 Affymetrix technology, we evaluated genetic copy number alteration events in a collection of 107 fine-needle microdissected breast cancers, including 82 triple-negative and 25 non-triple negative (17 ER+/ HER2- and 8 ER-/HER2+) samples. 18 blood samples from matching patients were also profiled and their pool was used as a baseline. Results: Upon application of circular binary segmentation algorithm, 36 and 190 chromosomal regions could be identified for being respectively frequently amplified and deleted in triple-negative tumors (frequency &amp;gt; 30%, p-value &amp;lt; 0.001). Our analysis confirms many regions, such as 1 p36, 3q26, 5q11, 8p23,17p13, already known to be amplified or deleted from previous studies. Using two- dimensional hierarchical clustering based on copy number changes of segmented DNA regions in all tumor samples, no particular chromosomal alteration appeared to classify the group of triple- negative breast cancer. However, through supervised analysis, specific DNA deletions could be identified that occur at significantly higher frequency in triple-negative tumors as compared to the non-triple negatives, mainly involving chromosomal regions 3p14, 4p15, 5q11, 5q12 and 5q13. Interestingly, these regions harbour a number of cancer-related miRNAs, such as miR-135a, miR-7g and miR-95. Conversely, regions 15q13,16q22,16q23 and 16q24 were observed to be preferentially deleted in non-triple negative tumors. We explored the biological pathways affected by genomic aberrations in triple negative and non-triple negative tumors, using a comparative gene set enrichment approach. The analysis was run on genes frequently amplified/deleted (&amp;gt; 30% of samples) in the two tumor groups. Among others, the “immunological response” pathway emerged as more frequently affected by events of amplification in triple-negative breast tumors (p-value &amp;lt; 0.001). In order to characterize functional dependencies between different genomic aberration events, we ran a co-occurrence analysis of genomic regions frequently altered in triple- negative tumors (&amp;gt;20%). A number of chromosome regions were identified for being frequently co-amplified. These include regions on chromosome 1q (with each other), 10p (with each other), 6q11 with 7p12 and 19q13,19q and 5p. Similarly, regions of co-deletions could be identified, such as: 8p21 (with each other), 4p15 (with each other), 17p13 and 5q11,6q26, and 17p12. Conclusions: We have performed a comprehensive survey of copy number variations in triple-negative breast tumors, pinpointing genomic regions and related genes and pathways specifically altered in this class of tumors. Dependencies between individual events of genomic amplification or deletion have been identified, suggesting they are resulting from selective pressure and their coordinated genomic alteration is required for the survival of the cancer cells involved. Our analyses shed further light on the genomically complex and heterogeneous nature of triple-negative tumors in relation to other subgroups of breast cancer. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B3.