K. Liang1, G. Gauvin1, E. O’Halloran1, D. Mutabdzic1, C. Mayemura1, E. McGillivray1, K. Loo1, A. Olszanski2, S. Movva2, M. Lango1, H. Wu3, B. Luo4, J. D’Souza5, S. Reddy1, J. Farma1 1Fox Chase Cancer Center,Department Of Surgical Oncology,Philadelphia, PA, USA 2Fox Chase Cancer Center,Department Of Hematology/Oncology,Philadelphia, PA, USA 3Fox Chase Cancer Center,Department Of Pathology,Philadelphia, PA, USA 4Fox Chase Cancer Center,Molecular Diagnostics Laboratory,Philadelphia, PA, USA 5Fox Chase Cancer Center,Molecular Therapeutics Program,Philadelphia, PA, USA
Introduction: Mitotic rate (MR) is a measure of tumor cellular proliferation in melanoma and has been associated with the tumor’s likelihood to metastasize. Although higher mitotic rate is associated with worse prognosis, specific genetic mutations associated with MR are less known. In this study, we examine the relationship between mitotic rate and genetic mutations in melanoma using next generation sequencing (NGS) technology.
Methods: A retrospective chart review was conducted on all melanoma patients who received NGS and had pathology reports with documented mitotic rates at an NCI designated cancer center. We compared no mitosis versus ≥ 5 mitoses. Groups were compared using chi squared tables and linear regression models.
Results: Between 1997 and 2018, 239 melanoma patients had NGS performed and were included in this study. The median age of the study group was 64 and 62% were male. Primary tumor locations were trunk (n=70), lower extremity (n=59), upper extremity (n=50), head and neck (n=31), mucosal (n=10), genital (n=5), and other (n=14). Pathological staging included stage I (n=25), stage II (n=64), stage III (n=109), stage IV (n=20), and unknown (n=21). Only 5 patients had 0 mitoses/mm2, while 104 patients had ≥ 5 mitoses/mm2. Out of a total of 380 mutations, the most common gene mutations were any BRAF (18%, n=69) or NRAS (14%, n=53) mutation, but these were not associated with mitotic rate. Mutations in ERBB4, PIK3CA, and SMAD genes were protective against high mitotic rate, associated with 0 mitoses/mm2 (p=0.009, 0.002, 0.044, respectively). Higher mitotic rates, greater than 5/mm2, were associated with mutations in TP53 (p=0.015), KRAS (p=0.002), and FGFR3 (p=0.048). Only three patients had mutations in all three of these genes; these patients had 8, 9, and 20 mitoses/mm2 on final pathology. After controlling for mutations in KRAS and FGFR3, a mutation in TP53 is associated with 2.74-fold increased odds of having more than 5 mitoses/mm2 (95%CI 1.15-6.52, p=0.023).
Conclusion: Mitotic rate is an important prognostic indicator in melanoma. Our data demonstrate that certain genetic mutations such as TP53, FGFR3, and KRAS are associated with higher mitotic rate while other mutations, including ERBB4, PIK3CA, and SMAD4 are more frequently found in patients with no mitoses. Further studies are needed to determine whether next generation sequencing can be used to predict more aggressive tumors so that treatment and surveillance can be better tailored to these patients.