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06-02-2012 | Genetics | Article

Four-gene signature predicts oral carcinoma recurrence

Abstract

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MedWire News: A signature consisting of four upregulated genes can predict the recurrence of oral squamous cell carcinoma (OSCC), even in patients with clear resection margins, say researchers.

Failure to completely remove the primary tumor is the leading cause of death among patients with OSCC. The histologic presence of cancerous cells within the tumor margins is associated with a 66% increased risk for recurrence. However, even when margins are thought to be clear of cancer cells, recurrence occurs in 10-30% of patients.

Genetic analysis of OSCC surgical resection margins has revealed alterations in a large number of genes, some of which have been associated with increased tumor recurrence. However, to date, no attempt has been made to use these alterations clinically to predict which patients are at higher risk for disease recurrence.

In the current study, Igor Jurisica (Ontario Cancer Institute, Toronto, Canada), Suzanne Kamel-Reid (University of Ontario, Toronto, Canada) and colleagues performed microarray analysis on tissue samples from OSCC patients to determine a gene signature that could be used to predict tumor recurrence in these patients. All patients included in this study had a final pathology report of histologically normal margins.

To begin with, Jurisica, Kamel-Reid and colleagues used a 96-sample set from 24 OSCC patients, in addition to a meta-analysis of published studies, to identify likely candidates for the gene signature. A total of 138 genes were identified that were overexpressed in the surgical margins taken from these patients.

Of these 138 genes, four genes that contributed most to the risk score following Cox regression were selected: these were matrix metalloproteinase 1 (MMP1), Collagen alpha-1(IV) chain (COL4A1), Prolyl 4-hydroxylase subunit alpha-2 (P4HA2), and Thrombospondin-2 (THBS2).

In the next part of the study, published in BMC Cancer, the authors examined the value of a gene signature, consisting of the four identified genes, in predicting OSCC recurrence using 136 samples taken from 30 patients.

The analysis confirmed that all four genes are upregulated in the margins and tissue samples from OSCC patients with disease recurrence compared with samples from patients who did not experience recurrence. Overexpression of this four-gene signature in histologically normal margins was significantly associated with recurrence (hazard ratio=6.8).

Commenting on their findings the authors say: "This signature is based on genes found to be consistently overexpressed in OSCC as compared to normal oral mucosa; these genes are also overexpressed in a subset of histologically normal surgical resection margins, and their overexpression in such margins provides an indication of the presence of genetic changes before histological alterations can be detected."

Concluding, the authors say "Our data suggest that histologically normal surgical resection margins that over-express MMP1, COL4A1, THBS2 and P4HA2 are indicative of an increased risk of recurrence in OSCC."

By Iain Bartlett

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