Page 67 - New epidemiological and PSMA-expression based paradigms in salivary gland tumors

Malignant transformation of pleomorphic adenoma: Proof of principle
Figure 4. An identical pattern of allelic imbalance was found on chromosomes 5, 7 (shown in this figure) and 8. The imbalances are present in the primary pleomorphic adenoma, the first and the second recurrence. BAF = B-Allele Frequency.
Discussion
This report shows for the first time chronological genetic steps of progression of SGPA to a malignant salivary gland tumor, accompanied by the occurrence of TP53 mutations. The two lesions with different clonal TP53 mutations probably represent two different recurrences from the same tumor, as multinodular recurrence is common. TP53 mutations have been reported as the most frequent mutations in salivary gland carcinomas in general, followed by abnormalities in the cyclin and PI3K pathways (including PIK3R1)[25].
All lesions showed the same LIFR/PLAG1 gene fusion, PIK3R1 mutation and allelic imbalance pattern, revealing their origin from the primary SGPA. It is tempting to speculate that the combination of the LIFR/PLAG1 gene fusion and the PIK3R1 mutation with loss of the other allele were drivers for proliferation whereas the additional TP53 mutations initiated the malignant transformation. Additional support for this comes from a mouse model with overexpression of Plag1 targeted to salivary glands and hyperactivation of the PI3K pathway by a conditional salivary gland Pten knockout mouse model which both resulted in pleomorphic adenoma formation[26,27].
The occurrence of new TP53 mutations in the recurrences does not confirm a causal role for these mutations in malignant transformation since the specificity of TP53 mutation for this process is unknown. However, newly present TP53
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