Downregulation of CRNN gene and genomic instability at 1q21.3 in oral squamous cell carcinoma

• Published in: Clinical oral investigations Vol. 19; no. 9; pp. 2273 - 2283
• Main Authors: Salahshourifar, Iman, Vincent-Chong, Vui King, Chang, Hong-Yun, Ser, Hooi Leng, Ramanathan, Anand, Kallarakkal, Thomas George, Rahman, Zainal Ariff Abdul, Ismail, Siti Mazlipah, Prepageran, Narayanan, Mustafa, Wan Mahadzir Wan, Abraham, Mannil Thomas, Tay, Keng Kiong, Zain, Rosnah Binti
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2015; Springer Nature B.V
• Subjects: Carcinoma, Squamous Cell - genetics; Dentistry; Down-Regulation; Genomic Instability; Humans; Immunohistochemistry; Loss of Heterozygosity; Malaysia; Medicine; Membrane Proteins - genetics; Microsatellite Instability; Mouth Neoplasms - genetics; Neoplasm Proteins - genetics; Original Article; Polymerase Chain Reaction; Prognosis; Oral squamous cell carcinoma; Genetic instability; gene; 1q23.1. LOH/MSI; CRNN gene
• ISSN: 1432-6981; 1436-3771
• DOI: 10.1007/s00784-015-1467-7

Objectives
This study includes the direct sequencing of cornulin (CRNN) gene to elucidate the possible mechanism of
CRNN
downregulation and explore the genetic imbalances at 1q21.3 across oral squamous cell carcinoma (OSCC) samples.
Materials and methods
In mutation screening of
CRNN
gene, gDNA from OSCC tissues were extracted, amplified, and followed by direct sequencing. OSCC samples were also subjected to fragment analysis on
CRNN
gene to investigate its microsatellite instability (MSI) and loss of heterozygosity (LOH). Immunohistochemistry was performed to validate CRNN downregulation in OSCC samples.
Results
No pathogenic mutation was found in
CRNN
gene, while high frequency of allelic imbalances was found at 1q21.3 region. MSI was found more frequent (25.3 %) than LOH (9.3 %). Approximately 22.6 % of cases had high MSI which reflects higher probability of inactivation of DNA mismatch repair genes. MSI showed significant association with no betel quid chewing (
p
 = 0.003) and tongue subsite (
p
 = 0.026). LOH was associated with ethnicity (
p
 = 0.008) and advanced staging (
p
 = 0.039). The LOH at 1q21.3 was identified to be as an independent prognostic marker in OSCC (HRR = 7.15 (95 % CI, 1.41–36.25),
p
 = 0.018). Downregulation of CRNN was found among MSI-positive OSCCs and was associated with poor prognosis (
p
 = 0.044).
Conclusion
This study showed a significant correlation between LOH/MSI at 1q21.3 with clinical outcomes and that downregulation of
CRNN
gene could be considered as a prognostic marker of OSCC.
Clinical relevance
Insights of the downregulation mode of
CRNN
gene lays the basis of drug development on this gene as well as revealing its prognostic value.