Genomic profiling of advanced-stage oral cancers reveals chromosome 11q alterations as markers of poor clinical outcome

Abstract

Identifying oral cancer lesions associated with high risk of relapse and predicting clinical outcome remain challenging questions in clinical practice. Genomic alterations may add prognostic information and indicate biological aggressiveness thereby emphasizing the need for genome-wide profiling of oral cancers. High-resolution array comparative genomic hybridization was performed to delineate the genomic alterations in clinically annotated primary gingivo-buccal complex and tongue cancers (n = 60). The specific genomic alterations so identified were evaluated for their potential clinical relevance. Copy-number changes were observed on chromosomal arms with most frequent gains on 3q (60%), 5p (50%), 7p (50%), 8q (73%), 11q13 (47%), 14q11.2 (47%), and 19p13.3 (58%) and losses on 3p14.2 (55%) and 8p (83%). Univariate statistical analysis with correction for multiple testing revealed chromosomal gain of region 11q22.1-q22.2 and losses of 17p13.3 and 11q23-q25 to be associated with loco-regional recurrence (P = 0.004, P = 0.003, and P = 0.0003) and shorter survival (P = 0.009, P = 0.003, and P 0.0001) respectively. The gain of 11q22 and loss of 11q23-q25 were validated by interphase fluorescent in situ hybridization (I-FISH). This study identifies a tractable number of genomic alterations with few underlying genes that may potentially be utilized as biological markers for prognosis and treatment decisions in oral cancers.

Figure 1. Radial heatmap of recurring copy-number alterations (CNAs) in OSCC.

Shown in the inner heatmap are copy number gains/amplifications (blue) and losses/deletions (red), where tumors are stacked radially. Significantly recurring alterations (RAE q-value <0.1) are displayed between the outermost chromosome ideograms and the inner heat map (red: losses, blue: gains). Open circles denote known copy-number variants (CNVs) that span more than 50% with recurring CNAs. Chromosome numbers are shown in bold at periphery of chromosome ideograms with genomic coordinates in megabases.

Figure 2. Array CGH based identification of 9p23-p24.1 loss encompassing putative tumor suppressor gene PTPRD.

Figure 3. Patient survival curves and FISH validation of 11q23-q25 loss.

A) Kaplan-Meier survival estimates of patient groups with and without loss of chromosome 11q23–q25; survival in months (x-axis) is plotted against the fraction of samples alive (y-axis). Interphase FISH analysis detecting the chromosome 11 centromere (red) and the 11q24.1 region (green), B) A case without 11q24.1 loss and C) A case of 11q24.1 loss are shown.

Figure 4. Patient survival curves and FISH validation of 11q22.1-q22.2 gain.

A) Kaplan-Meier survival estimates of patient groups with and without gain of chromosome 11q22.1–q22.2; survival in months (x-axis) is plotted against the fraction of samples alive (y-axis). Interphase FISH analysis detecting the chromosome 11 centromere (red) and the 11q22.1–q22.2 region (green), B) A case without 11q22.1-q22.2 gain and C) A case of 11q22.1–q22.2 gain are shown.