MTAP deficiency is common in head and neck tumors but dependent on the site of tumor origin

Head and neck cancers (HNCs) represent a heterogeneous group of malignancies with highly variable clinical outcomes. Despite advances in surgery, radiotherapy, and systemic treatments, more than 300,000 patients still die from HNC every year worldwide. S-methyl-5′-thioadenosine phosphorylase (MTAP) is encoded by the MTAP gene located at 9p21 and is often homozygously co-deleted in cancer together with cyclin dependent kinase 2A ( CDKN2A ). MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting multiple pathways. Since MTAP is ubiquitously expressed and homozygous MTAP deletions result in a complete expression loss, MTAP immunohistochemistry (IHC) can be used for its detection. To evaluate the prevalence and clinical significance of MTAP expression loss in head and neck cancer, a total of 583 carcinomas were analyzed by immunohistochemistry (IHC) in a tissue microarray format. MTAP expression was lost (0+; MTAP deficiency) in 15.2%, weak (1+) in 31.2%, moderate (2+) in 29.7%, and strong (3+) in 23.9% of 508 interpretable head and neck carcinomas. The prevalence of MTAP deficiency varied markedly between tumors of different sites of origin. MTAP deficiency occurred in 36.0% of 25 cancers of the hypopharynx, 27.0% of 126 cancers of the larynx, 33.3% of 6 carcinomas of the oral cavity, 21.4% of 14 carcinomas of the nasopharynx, but only 8.6% in 336 carcinomas of the oropharynx (p<0.0001). MTAP deficiency tended to be more prevalent in tumors of high pT-stage (p=0.0923) and in patients with concomitant metastases (M1; p=0.0625) but these differences did not reach a level of statistical significance. MTAP deficiency was unrelated to histologic grade of malignancy, nodal metastasis, L-status, and V-status. Among 432 head and neck cancers lacking MTAP deficiency, the level of MTAP expression (1+ vs 2+ vs. 3+) was unrelated to parameters of cancer aggressiveness. It is concluded from our data, that MTAP deficiency occurs in a relevant fraction of head and neck cancers. Once anti-MTAP treatments should become safe and efficient and approved for patient treatment, many patients with these tumors could benefit. Moreover, IHC analysis for MTAP deficiency appears to have diagnostic utility in assessing dysplasia, given its high prevalence in grade 1 carcinomas.