One of the most important components of G1 checkpoint is the retinoblastoma protein (pRB 110 ). The activity of pRB is regulated by its phosphorylation, which is mediated by genes such as cyclin D1 and p16 / MTS1 . All three genes have been shown to be commonly altered in human malignancies. We have screened a panel of 26 oral squamous cell carcinomas (OSCC), nine premalignant and three normal oral tissue samples as well as eight established OSCC cell lines for mutations in the p16 / MTS1 gene. The expression of p16 / MTS1 , cyclin D1 and pRB 110 was also studied in the same panel. We have found p16 / MTS1 gene alterations in 5/26 (19%) primary tumours and 6/8 (75%) cell lines. Two primary tumours and five OSCC cell lines had p16/MTS1 point mutations and another three primary and one OSCC cell line contained partial gene deletions. Six of seven p16/MTS1 point mutations resulted in termination codons and the remaining mutation caused a frameshift. Western blot analysis showed absence of p16/MTS1 expression in 18/26 (69%) OSCC, 7/9 (78%) premalignant lesions and 8/8 cell lines. One cell line, H314, contained a frameshift mutation possibly resulting in a truncated p16/MTS1 protein. pRB was detected in 14/25 (56%) of OSCC but only 11/14 (78%) of these contained all or some hypophosphorylated (active) pRB. In premalignant samples, 6/8 (75%) displayed pRB, and all three normal samples and eight cell lines analysed contained RB protein. p16/MTS1 protein was undetectable in 10/11 (91%) OSCCs with positive pRB. Overexpression of cyclin D1 was observed in 9/22 (41%) OSCC, 3/9 (33%) premalignant and 8/8 (100%) of OSCC cell lines. Our data suggest p16/MTS1 mutations and loss of expression to be very common in oral cancer cell lines and less frequent in primary OSCC tumours. A different pattern of p16/MTS1 mutations was observed in OSCC compared to other cancers with all the detected p16/MTS1 mutations resulting in premature termination codons or a frameshift. The RB protein was expressed in about half (44%) of OSCCs and its expression inversely correlated with p16/MTS1 expression. In conclusion, we show that abnormalities of the RB pathway are a common mechanism of oral carcinogenesis. © 1999 Cancer Research Campaign

Lysyl oxidase (LO) takes part in the initial steps of converting soluble monomers of collagen and elastin into insoluble fibres in the extracellular matrix. We have studied the immunolocalization of LO as a marker of fibrogenesis in oral submucous fibrosis (OSF). Oral biopsies from 13 subjects with OSF, 6 with histologically confirmed squamous cell carcinoma (SCC) arising in OSF and 10 SCC non‐related to OSF, were examined. Strong positive staining was observed in 7/13 OSF samples in the cytoplasmic processes of fibroblasts and extracellularly in the upper third of the lamina propria. Furthermore, LO was found to co‐localize in the areas stained strongly for collagen and elastin by histochemical stains. Examination of SCC tissues showed localization of LO adjacent to invading epithelial islands as evidence of a stromal reaction both in carcinomas arising from OSF and in SCC from non‐OSF cases. These findings suggest that upregulation of LO may be an important factor in the pathogenesis of OSF and in the early stromal reaction of oral cancer.

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Summary Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on Sq was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on Sq also harbouring a TP53 mutation. LOH on Sq was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas.