Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer

<div><p>For the rabphillin-3A-like (<i>RPH3AL</i>) gene, a putative tumor suppressor, the clinical significance of genetic alterations in breast cancers was evaluated. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) cancers and matching normal tissues. DNA samples were assessed for loss of heterozygosity (LOH) at the <i>17p13</i>.<i>3</i> locus of <i>RPH3AL</i> and the <i>17p13</i>.<i>1</i> locus of the tumor suppressor, <i>TP53</i>. <i>RPH3AL</i> was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of <i>RPH3AL</i>, and FFPE tissues were profiled for its phenotypic expression. Alterations in <i>RPH3AL</i> were correlated with clinicopathological features, LOH of <i>TP53</i>, and patient survival. Of 121 cancers, 80 had LOH at one of the <i>RPH3AL</i> locus. LOH of <i>RHP3AL</i> was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the <i>RPH3AL</i> and <i>TP53</i> loci, 19 of 105 exhibited LOH only at the <i>RPH3AL</i> locus. Of these, 12 were non-Hispanic Caucasians (Whites), 15 had large tumors, and 12 were older (>50 years). Patients exhibiting LOH at both loci had shorter survival than those without LOH at these loci (log-rank, P = 0.014). LOH at the <i>TP53</i> locus alone was not associated with survival. Analyses of <i>RPH3AL</i> identified missense point mutations in 19 of 125 cases, a SNP (C>A) in the 5’untranslated region at -25 (5’UTR-25) in 26 of 104, and a SNP (G>T) in the intronic region at 43 bp downstream to exon-6 (intron-6-43) in 79 of 118. Genotype C/A or A/A of the SNP at 5’UTR-25 and genotype T/T of a SNP at intron-6-43 were predominantly in Whites. Low levels of RNA and protein expression of <i>RPH3AL</i> were present in cancers relative to normal tissues. Thus, genetic alterations in <i>RPH3AL</i> are associated with aggressive behavior of breast cancers and with short survival of patients.</p></div>