In the USA, more people die from oral squamous cell carcinoma (SCC) than melanoma, cervical or ovarian cancer and the incidence, particularly in young people, is increasing. Neck metastasis is the primary cause of death;however, not all oral SCCs metastasize. Due to the current poor accuracy in detecting metastasis by clinical or radiographic examination prior to surgical removal of the primary cancer, neck dissection, surgery to remove the cervical (neck) lymph nodes is performed if the metastatic risk is >20% based on current risk assessment capability. Therefore, almost all oral SCC patients undergo a neck dissection which increases patient morbidity. Recent studies in our laboratories have discriminated two oral SCC subtypes with distinct molecular signatures and metastatic rates. One subtype, the 3q8pq20 subtype, is characterized by the presence of one or more of the recurrent copy number aberrations, +3q, - 8p, +8q and/or +20. The other subtype (non-3q8pq20) lacks these copy number alterations. The non-3q8pq20 subtype is associated with a low risk of metastasis (7%) compared to the 46% rate of metastasis in the 3q8pq20 subtype. This observation has been replicated in an independent oral SCC cohort. Thus, DNA copy number alterations at one or more of these loci is a biomarker identifying a group of patients at low risk for metastasis, who could be spared the potentially unnecessary major surgery required for removal of the cervical lymph nodes. In response to PA-09-158, we are proposing to develop our DNA copy number signature (+3q, -8p, +8q, +20) as a clinical test to identify the non-3q8pq20 subset of patients at low risk for metastasis. To this end, we will develop and validate a FISH-based assay to detect DNA copy number for chromosomes 3q, 8p, 8q and 20 that is suitable for analysis of lesional brush biopsies collected prior to surgery. Work will focus on sample collection (Aim 1) and copy number detection by FISH (Aim 2). We seek the combination of specimen collection technique and analysis technology that would be best suited for clinical implementation. The validated and optimized assay will be used to assess 3q8pq20 status in a subsequent multi-institutional prospective trial to establish the utility of this biomarker to identify patients who do not require a neck dissection.
Neck metastasis is the primary determinant for prognosis of oral cancer patients. Here, an assay for a recently identified molecular signature for tumors with low risk of metastasis will be validated and developed into a clinical test. The assay format will be suitable for analysis of patient samples collected during the period of patient evaluation prior to surgery in order to allow clinicians to confidently identify those patients at low risk for neck metastasis, who, at the time of surgical removal of their tumors, could be spared the additional major surgery required to remove the neck lymph nodes.
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|Scheinin, Ilari; Sie, Daoud; Bengtsson, Henrik et al. (2014) DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res 24:2022-32|