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

Putcha BD, Jia X, Katkoori VR, Salih C, Shanmugam C, Jadhav T, Bovell LC, Behring MP, Callens T, Messiaen L, Bae S, Grizzle WE, Singh KP, Manne U - PLoS ONE (2015)

Bottom Line: LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival.LOH at the TP53 locus alone was not associated with survival.Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Prognostic significance of RPH3AL LOH.Kaplan-Meier survival analyses of (A) LOH at 17p13.3 locus of RPH3AL, (B) LOH at 17p13.1 locus of the TP53, and (C) combinations of LOH at RPH3AL and TP53, and (D) survival proportions of patients with LOH at both RPH3AL and TP53 loci versus the patients without LOH at both loci. Log-rank P-values and the number of patients at risk (N) in each group at different time periods. Positivity of RPH3AL LOH, but not TP53 LOH, was associated with patient poor survival. Patients with LOH positivity at both RPH3AL and TP53 loci had poor survival relative to patients with LOH at TP53 and without LOH at RPH3AL (P = 0.008) as well as those that were LOH negative at both loci (P = 0.014). Also, the subgroup with LOH positive at RPH3AL and LOH negative at TP53 locus had poor survival, similar to the patients that were positive at both loci (P = 0.101), suggesting that RPH3AL LOH is associated with patient prognosis.
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pone.0129216.g002: Prognostic significance of RPH3AL LOH.Kaplan-Meier survival analyses of (A) LOH at 17p13.3 locus of RPH3AL, (B) LOH at 17p13.1 locus of the TP53, and (C) combinations of LOH at RPH3AL and TP53, and (D) survival proportions of patients with LOH at both RPH3AL and TP53 loci versus the patients without LOH at both loci. Log-rank P-values and the number of patients at risk (N) in each group at different time periods. Positivity of RPH3AL LOH, but not TP53 LOH, was associated with patient poor survival. Patients with LOH positivity at both RPH3AL and TP53 loci had poor survival relative to patients with LOH at TP53 and without LOH at RPH3AL (P = 0.008) as well as those that were LOH negative at both loci (P = 0.014). Also, the subgroup with LOH positive at RPH3AL and LOH negative at TP53 locus had poor survival, similar to the patients that were positive at both loci (P = 0.101), suggesting that RPH3AL LOH is associated with patient prognosis.

Mentions: Kaplan-Meier analysis of the breast cancers demonstrated that patients with LOH-positive tumors had poor survival relative to patients with LOH-negative tumors (log rank, P = 0.039) (Fig 2A). Since TP53, located in proximity to RPH3AL within the 17p chromosomal region, is a driver gene and exhibits LOH in breast cancers, the TP53 LOH status of breast cancer cohorts was analyzed. Of the 127 cases analyzed for LOH status at the 17p13.1 locus of TP53, 105 cases were informative for LOH, and 22 cases were homozygous at the loci. In the FFPE cohort, there was no significant difference in the survival probability between TP53 LOH-positive and-negative patient groups (log rank, P = 0.530) (Fig 2B).


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

Putcha BD, Jia X, Katkoori VR, Salih C, Shanmugam C, Jadhav T, Bovell LC, Behring MP, Callens T, Messiaen L, Bae S, Grizzle WE, Singh KP, Manne U - PLoS ONE (2015)

Prognostic significance of RPH3AL LOH.Kaplan-Meier survival analyses of (A) LOH at 17p13.3 locus of RPH3AL, (B) LOH at 17p13.1 locus of the TP53, and (C) combinations of LOH at RPH3AL and TP53, and (D) survival proportions of patients with LOH at both RPH3AL and TP53 loci versus the patients without LOH at both loci. Log-rank P-values and the number of patients at risk (N) in each group at different time periods. Positivity of RPH3AL LOH, but not TP53 LOH, was associated with patient poor survival. Patients with LOH positivity at both RPH3AL and TP53 loci had poor survival relative to patients with LOH at TP53 and without LOH at RPH3AL (P = 0.008) as well as those that were LOH negative at both loci (P = 0.014). Also, the subgroup with LOH positive at RPH3AL and LOH negative at TP53 locus had poor survival, similar to the patients that were positive at both loci (P = 0.101), suggesting that RPH3AL LOH is associated with patient prognosis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466565&req=5

pone.0129216.g002: Prognostic significance of RPH3AL LOH.Kaplan-Meier survival analyses of (A) LOH at 17p13.3 locus of RPH3AL, (B) LOH at 17p13.1 locus of the TP53, and (C) combinations of LOH at RPH3AL and TP53, and (D) survival proportions of patients with LOH at both RPH3AL and TP53 loci versus the patients without LOH at both loci. Log-rank P-values and the number of patients at risk (N) in each group at different time periods. Positivity of RPH3AL LOH, but not TP53 LOH, was associated with patient poor survival. Patients with LOH positivity at both RPH3AL and TP53 loci had poor survival relative to patients with LOH at TP53 and without LOH at RPH3AL (P = 0.008) as well as those that were LOH negative at both loci (P = 0.014). Also, the subgroup with LOH positive at RPH3AL and LOH negative at TP53 locus had poor survival, similar to the patients that were positive at both loci (P = 0.101), suggesting that RPH3AL LOH is associated with patient prognosis.
Mentions: Kaplan-Meier analysis of the breast cancers demonstrated that patients with LOH-positive tumors had poor survival relative to patients with LOH-negative tumors (log rank, P = 0.039) (Fig 2A). Since TP53, located in proximity to RPH3AL within the 17p chromosomal region, is a driver gene and exhibits LOH in breast cancers, the TP53 LOH status of breast cancer cohorts was analyzed. Of the 127 cases analyzed for LOH status at the 17p13.1 locus of TP53, 105 cases were informative for LOH, and 22 cases were homozygous at the loci. In the FFPE cohort, there was no significant difference in the survival probability between TP53 LOH-positive and-negative patient groups (log rank, P = 0.530) (Fig 2B).

Bottom Line: LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival.LOH at the TP53 locus alone was not associated with survival.Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus