title: Discordance of genetic alterations between primary head and neck tumors and corresponding metastases associated with mutational status of the TP53 gene.
abstract: Ample molecular data are available on the progression from normal mucosa to invasive head and neck squamous cell carcinoma (HNSCC), but information on further genetic progression to metastatic disease is scarce. To obtain insight into the metastatic process, we compared 23 primary HNSCCs with 25 corresponding lymph node metastases (LNMs) and 10 corresponding distant metastases (DMs) with respect to TP53 mutations and patterns of loss of heterozygosity (LOH) based on 26 microsatellite markers on six chromosome arms (3p, 9p, 17p, 13q, 8p, and 18q). In 18 of the 23 patients, a TP53 mutation was detected in the primary tumor, and in all cases the same TP53 mutation was present in the corresponding LNM or DM. In nine of 20 patients with LNMs and three of seven patients with DMs, the LOH pattern of metastasis differed from that of the corresponding primary tumor by at least one marker. Microsatellite markers located on chromosome arms 13q, 8p, and 18q were most frequently discordant, providing evidence that alterations at these chromosomes occur late in HNSCC carcinogenesis. Moreover, evidence was found that DMs had developed directly from the primary tumor and not from LNMs. Remarkably, we observed that the mutational status of the TP53 gene is associated significantly with the degree of genetic differences between primary HNSCCs and corresponding metastases. All patients with TP53 wild-type primary tumors showed significantly more discordant LOH patterns in the corresponding LNMs and DMs than patients with TP53-mutated tumors. The percentages were 100% versus 27% (LNMs) and 100% versus 0% (DMs), respectively (P = 0.008 and P = 0.029; two-sided Fisher exact test). This finding suggests that TP53-mutated tumors need fewer additional genetic alterations to develop metastases compared with TP53 wild-type primary tumors.
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, Amsterdam, Netherlands.
authors.forename: Maarten P
authors.initials: MP
authors.lastname: Tabor
authors.forename: Viola M M
authors.initials: VM
authors.lastname: van Houten
authors.forename: J Alain
authors.initials: JA
authors.lastname: Kummer
authors.forename: Maria J W D
authors.initials: MJ
authors.lastname: Vosjan
authors.forename: Ronald
authors.initials: R
authors.lastname: Vlasblom
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Snow
authors.forename: C René
authors.initials: CR
authors.lastname: Leemans
authors.forename: Boudewijn J M
authors.initials: BJ
authors.lastname: Braakhuis
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
mesh_terms: D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006338:Heart Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D019656:Loss of Heterozygosity / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D013160:Splenic Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary