Abstract
BackgroundMany alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified.ResultsWe studied 307 primary breast tumors and 47 breast cancer cell lines by high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 lost in about 20% of the tumors and 40% of the cell lines. The minimal common region of loss (Chr18:6,366,938-6,375,929 bp) targeted the L3MBTL4 gene. This gene was also targeted by breakage in one tumor and in two cell lines. We studied the exon sequence of L3MBTL4 in 180 primary tumor samples and 47 cell lines and found six missense and one nonsense heterozygous mutations. Compared with normal breast tissue, L3MBTL4 mRNA expression was downregulated in 73% of the tumors notably in luminal, ERBB2 and normal-like subtypes. Losses of the 18p11 region were associated with low L3MBTL4 expression level. Integrated analysis combining genome and gene expression profiles of the same tumors pointed to 14 other potential 18p TSG candidates. Downregulated expression of ZFP161, PPP4R1 and YES1 was correlated with luminal B molecular subtype. Low ZFP161 gene expression was associated with adverse clinical outcome.ConclusionWe have identified L3MBTL4 as a potential TSG of chromosome arm 18p. The gene is targeted by deletion, breakage and mutations and its mRNA is downregulated in breast tumors. Additional 18p TSG candidates might explain the aggressive phenotype associated with the loss of 18p in breast tumors.
Highlights
Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG)
Losses and breakages of 18p targets the L3MBTL4 gene at p11.31 Genome profiles of 307 primary breast tumors and 47 cancer cell lines were established by array comparative genomic hybridization (aCGH)
L3MBTL4 mRNA is downregulated in breast tumors L3MBTL4 gene expression was measured using qRTPCR in normal breast tissues and 52 breast tumor samples including 16 with a loss of the L3MBTL4 gene region (T7420, T8009, T8189, T8600, T8700, T9059, T9398, T9888, T9941, T11348, T11485, T11568, T10684, T12854, T13469, T13018), one mutated and deleted (T10003), and one mutated but not deleted (T8525)
Summary
Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified. The development and progression of breast cancer is the result of the accumulation of genetic alterations such as amplification of oncogenes and deletions of tumor suppressor genes (TSG) in the epithelial cells of the mammary gland. We profiled a series of 307 primary breast tumors and 47 breast cancer cell lines by using high resolution array comparative genomic hybridization (aCGH). We identified a region on 18p11.31 deleted in 25% of the tumors. To document the involvement of L3MBTL4 in breast cancer we searched for mutations by sequence analysis of 180 primary tumor samples and 47 cell lines. We found that L3MBTL4 deletions correlate with low mRNA expression and with the presence of lymph node metastasis, high ScarfBloom-Richardson (SBR) grade and luminal B molecular subtype
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