The presence of tumor infiltrating lymphocytes is a favorable prognostic factor in cutaneous melanoma, but their clinicopathological significance in the intratumoral compartment compared to the peritumoral compartment is unclear.,We investigated the clinicopathologic significance of tumor-infiltrating lymphocytes and lymphocyte score in intra- and peritumoral compartments in 177 Korean patients who had undergone surgical excision of cutaneous melanoma.,No significant correlation was observed between various clinicopathologic factors and the presence of intratumoral lymphocytes.,However, high peritumoral lymphocyte scores were associated with lower Clark levels (P = 0.001), shallower Breslow thicknesses (P = 0.006), and fewer mitotic counts (P = 0.01) than tumors with lower scores.,There was a trend for longer disease-free survival in cases with peritumoral lymphocytes (P = 0.07) than those without peritumoral lymphocytes.,In patients with acral lentiginous melanoma, a strong association between a high peritumoral lymphocyte score and shallow Clark level was apparent (P = 0.03), and the presence of peritumoral lymphocytes (P = 0.02) and a high intratumoral lymphocyte score (P = 0.04) was also associated with longer disease-free survival.,Particularly, low intratumoral lymphocyte score remarkably affected tumor recurrence and distant metastasis in a multivariate analysis using Cox regression test (H.R.,= 0.304, 95% C.I.,= 0.078-1.185, P = 0.09).,Thus, the presence of lymphocytes and high lymphocyte scores in the intratumoral and peritumoral compartments are valid prognostic factors in cutaneous melanoma.
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas.,Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas.,Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS.,Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas.,This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain.,Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration.,These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.