Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway

Shain, A. Hunter; Garrido, María C.; Botton, Thomas; Talevich, Eric; Yeh, Iwei; Sanborn, J. Zachary; Chung, Jongsuk; Wang, Nicholas J.; Kakavand, Hojabr; Mann, Graham J.; Thompson, John F.; Wiesner, Thomas; Roy, Ritu; Olshen, Adam B.; Gagnon, Alexander; Gray, Joe W.; Huh, Nam; Hur, Joe S.; Busam, Klaus J.; Scolyer, Richard A.; Cho, Raymond J.; Murali, Rajmohan; Bastian, Boris C.

doi:10.1038/ng.3382

Cited by 225 publications

(212 citation statements)

References 40 publications

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“…Mutational load was a positive prognostic feature in BLCA and in SKCM, and on the opposite end of the spectrum, a high mutational density was an adverse prognostic feature in pancreatic carcinoma, and a similar trend was observed in KIRC. A high mutational load has recently been associated with the desmoplastic variant of SKCM (42). Additionally, desmoplastic melanoma is known to have a better survival than other melanoma subtypes (43).…”

Section: Pd-1/pd-l Axis Expression Associates With Multiple Other Cosmentioning

confidence: 99%

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Danilova

Wang

Sunshine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

118

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Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzedPD-L1,PD-L2,PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database. We found that in some tumor types,PD-L2expression is more closely linked toTh1/IFNGexpression and PD-1 and CD8 signaling thanPD-L1. In contrast, mutational load was not correlated with aTh1/IFNGgene signature in any tumor type.PD-L1,PD-L2,PD-1,CYTexpression, and mutational density are all positive prognostic features in melanoma, and conditional inference modeling revealedPD-1/CYTexpression (i.e., an inflamed tumor microenvironment) as the most impactful feature, followed by mutational density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti–PD-1/PD-L1 will benefit from tumor-type–specific, integrated, mRNA, protein, and genomic approaches.

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Section: Pd-1/pd-l Axis Expression Associates With Multiple Other Cosmentioning

confidence: 99%

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Danilova

Wang

Sunshine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

148

118

View full text Add to dashboard Cite

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“…[1][2][3][4] We observed 9 BRAF-mutated patients (18%), with 4 (8%) having the mutation at known activating and druggable site p.Val600Glu. 31,32 In 4 patients, kinase-inhibiting BRAF mutations were identified, known to paradoxically activate the MAPK pathway via c-RAF (Gly466Val, 33 Gly469Arg, 34 and Asp594Asn 35 [present in 2 patients]). Two patients showed additional activating mutations in NRAS and KRAS, respectively, and 1 patient harbored 2 BRAF mutations (Lys499Asn and Glu695Lys) (supplemental Table 2).…”

Section: Ras Pathway-kras/nras/brafmentioning

confidence: 99%

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

Kortüm

Elias

Hanafiah

et al. 2016

Blood

194

189

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• The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM.• Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response. (Blood. 2016;128(9):1226-1233

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“…There were numerous point mutations reflective of ultraviolet radiation, a finding that is consistent with the high sun exposure associated with most desmoplastic melanomas. 28 Despite differences in initiating oncogenes, there were strong similarities among the later mutations that accumulated during subsequent stages of progression. TERT promoter mutations emerged early in intermediate lesions and melanomas in situ, occurring in 77% of these neoplasms (Fig.…”

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confidence: 99%

The Genetic Evolution of Melanoma from Precursor Lesions

et al. 2015

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Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway

Cited by 225 publications

References 40 publications

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

The Genetic Evolution of Melanoma from Precursor Lesions

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