Kunihiro Myo

Cyclin D1 gene numerical aberration is a predictive marker for occult cervical lymph node metastasis in TNM Stage I and II squamous cell carcinoma of the oral cavity.

The management of occult cervical lymph node metastases originating from oral squamous cell carcinomas (OSCCs) remains controversial. The purpose of this study was to evaluate the value of cyclin D1 gene (CCND1) numerical aberrations in predicting the risk of late lymph node metastases.

Fluorescence in situ hybridization for detecting genomic alterations of cyclin D1 and p16 in oral squamous cell carcinomas

Cyclin D1 (CCND1) and p16 alterations have been detected in oral squamous cell carcinomas (SCCs), suggesting that abnormalities of these genes may play an important role in the genesis or progression of oral SCCs and serve as independent prognostic indicators. The detection of CCND1 and p16 aberrations using a simple and sensitive method would be valuable for the development of effective treatment modalities for oral cancer. The objective of the current study was to determine whether CCND1 numerical aberrations and p16 deletions in oral SCCs detected by fluorescence in situ hybridization (FISH) have any impact on clinical outcome.

Prognostic utility of chromosomal instability detected by fluorescence in situ hybridization in fine-needle aspirates from oral squamous cell carcinomas

BackgroundAlthough chromosomal instability (CIN) has been detected in many kinds of human malignancies by means of various methods, there is no practical assessment for small clinical specimens. In this study, we evaluated CIN in fine-needle aspiration (FNA) biopsied oral squamous cell carcinomas (SCCs) using fluorescence in situ hybridization (FISH) analysis, and investigated its prognostic significance.MethodsTo evaluate CIN status of tumors, FISH with genomic probes for the centromeres of chromosomes 7, 9, and 11 was performed on specimens obtained by FNA from 77 patients with primary oral SCCs.ResultsHigh-grade CIN (CIN3) was observed in 11.7% (9/77) of patients with oral SCCs and was associated significantly with reduced disease-free survival (p = .008) and overall survival (p = .003). Multivariate Cox proportional hazards analysis showed that CIN status was significantly correlated with disease-free survival (p = .035) and overall survival (p = .041).ConclusionAnalysis of CIN status using FISH on FNA biopsy specimens may be useful in predicting of recurrence and poor prognosis in patients with oral SCCs.

Simultaneous Assessment of Cyclin D1 and Epidermal Growth Factor Receptor Gene Copy Number for Prognostic Factor in Oral Squamous Cell Carcinomas

Abstract Cyclin D1 gene ( CCND1 ) numerical aberrations are independent prognostic indicators of head and neck squamous cell carcinomas (HNSCCs). High epidermal growth factor receptor gene ( EGFR ) copy number is associated with poor prognosis in lung cancer, but such findings are controversial in oral SCCs (OSCCs). We analyzed copy number status in CCND1 and EGFR in OSCC patients and its association with clinical outcome. EGFR and CCND1 statuses were analyzed in 85 OSCC patients by fluorescence in situ hybridization (FISH) of specimens obtained by fine-needle aspiration biopsy. CCND1 numerical aberration was found in 35 of 85 tumors (41%), and aberrant EGFR copy number was observed in 36 (42%). Gene amplification (GA) was dominant among CCND1 copy number changes (14/35:40%). Balanced trisomy (BT) was the most frequently observed EGFR aberration (17/36:47%). In a multivariate Coxs proportional hazards analysis, CCND1 GA was correlated with disease-free survival ( P EGFR BT was significantly correlated with overall survival ( P = 0.001). Patients with a combination of CCND1 GA and/or EGFR BT had significantly poorer clinical outcome. CCND1 and EGFR copy number changes were frequent in OSCC and had differing aberration patterns. CCND1 GA and EGFR BT statuses by dual-color FISH were the predominant predictors of clinical outcome. Further investigation is needed to determine the implications for EGFR inhibitor therapy in OSCC.

Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis

Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large‐scale genetic profiling was performed on paired PT‐MLN samples obtained from 10 OTSCC patients using high‐density single‐nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy‐neutral loss‐of‐heterozygosity (CN‐LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT‐MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2‐3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN‐LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process.