Chromosomal imbalances in 113 primary head and neck squamous cell carcinomas (HNSCCs) determined by comparative genomic hybridization were correlated with patients survival using custom-made computer software which enabled the assessment of individual chromosomal loci. The Kaplan-Meier analysis revealed that overrepresentations of 2q12, 3q21-29, 6p21.1, 11q13, 14q23, 14q24, 14q31, 14q32, 15q24, 16q22, and deletions of 8p21-22 and 18q11.2 were significantly associated with both shorter disease-free interval and disease-specific survival in this tumor collective. Multivariate Cox proportional hazards regression models consistently identified the gains of 3q21-29, 11q13, and the loss of 8p21-22 as independent prognostic markers carrying a higher significance than the nodal status as the only clinicopathological parameter with statistical importance. In addition, these three markers allowed a molecular dissection of the patients with low clinical risk (pN0 and pT2 tumors). Thus, the genomic data being derived from the evaluation of primary HNSCC enabled a stratification of the patients into subgroups with different survival highlighting the necessity of a genetically based tumor classification for refining diagnosis and treatment of HNSCC patients. (Am J Pathol , :369 -375)

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Although rare, MPNST is one of the most aggressive tumors in the head and neck area. Complete tumor removal is the mainstay of treatment and most important prognostic factor of MPNST. Adjuvant radiotherapy should be used to assist surgical excision in local control. The role of adjuvant chemotherapy remains controversial.

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We have previously reported that the cyclin D1 (CCND1) GG 870 genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C 1722 polymorphism revealed that CCND1 CC 1722 genotype was associated with poorly differentiated tumors [P ‫؍‬ 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P ‫؍‬ 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG 870 genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P ‫؍‬ 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C 1722 genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG 870 genotype (P ‫؍‬ 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G 870 alleles, thus CCND1 transcript a was spliced equally from CCND1 A 870 and G 870 alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A 870 allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC 1722 genotype was more common in female patients (P ‫؍‬ 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square 1 , 3.96; P ‫؍‬ 0.046) and at higher levels (P ‫؍‬ 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G 870 alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender. (Am J Pathol 2001, 159:1917-1924)