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Background  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.    Results  We 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.    Conclusion  We 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.

Loss, mutation and deregulation of L3MBTL4 in breast cancers