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Abstract
For the rabphillin-3A-like (RPH3AL) 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 17p13.3 locus of RPH3AL and the 17p13.1 locus of the tumor suppressor, TP53. RPH3AL was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of RPH3AL, and FFPE tissues were profiled for its phenotypic expression. Alterations in RPH3AL were correlated with clinicopathological features, LOH of TP53, and patient survival. Of 121 cancers, 80 had LOH at one of the RPH3AL locus. LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the RPH3AL and TP53 loci, 19 of 105 exhibited LOH only at the RPH3AL 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 TP53 locus alone was not associated with survival. Analyses of RPH3AL 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 RPH3AL were present in cancers relative to normal tissues. Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.
Highlights
The human chromosomal region 17p shows frequent allelic loss/mutations in various cancers, including breast cancer [1,2,3,4]. 17p contains tumor suppressor genes such as TP53
Circulating anti-RPH3AL antibodies have been suggested as a diagnostic biomarker of colorectal cancers (CRCs) [20]
The T/T genotype of the intron-6-43 single nucleotide polymorphisms (SNPs) was observed at higher frequency in White patients. These findings suggest that the SNPs of RPH3AL are race-specific molecular markers for White patients with breast cancers
Summary
The human chromosomal region 17p shows frequent allelic loss/mutations in various cancers, including breast cancer [1,2,3,4]. 17p contains tumor suppressor genes such as TP53. In the absence of genetic alterations in TP53, breast cancers and other solid tumors exhibit genetic alterations in the telomeric region, including the 17p13.3 locus [5,6,7,8,9,10,11] Such genetic alterations indicate the existence of tumor suppressor genes in addition to TP53. Smith et al cloned, sequenced, and performed mutational analysis of RPH3AL gene in medulloblastoma, follicular thyroid carcinoma, and ovarian carcinoma [13]. As these studies failed to identify any missense mutations in RPH3AL, they concluded that RPH3AL was not involved in the oncogenesis of these neoplasms [13]. Circulating anti-RPH3AL antibodies have been suggested as a diagnostic biomarker of CRC [20]
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