Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma

Lee, Carolyn; Bhaduri, Aparna; Mah, Angela; Johnson, Whitney L.; Ungewickell, Alexander; Aros, Cody J.; Nguyen, Christie B; Rios, Eon J.; Siprashvili, Zurab; Straight, Aaron F.; Kim, Jinah; Aasi, Sumaira Z.; Khavari, Paul A.

doi:10.1038/ng.3091

Cited by 131 publications

(156 citation statements)

References 18 publications

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“…The top three recurrently altered genes are TP53, CDKN2A , and NOTCH1/2/4 , at frequencies similar to previous reports of both cSCCs (15, 16, 21, 22) and squamous cancers from other sites such as lung or HPV-negative head and neck (31, 32, 42, 61). TP53 was mutated in 79% of samples, CDKN2A altered in 48%, and NOTCH1/2/4 in 69%.…”

Section: Discussionsupporting

confidence: 85%

“…Similar findings were reported by studies involving larger cohorts of primary cSCCs: targeted sequencing of the known NOTCH1/2, TP53, CDKN2A, and RAS genes on 132 cSCCs that developed sporadically and 39 cSCCs that developed after BRAF-inhibitor treatment (20), and exome sequencing of 39 clinically aggressive cSCC primaries (21). Recently, missense mutations in the kinetochore-associated protein KNSTRN has emerged as a novel potential driver of cSCC, recurring in approximately 19% of cSCC cases (22). Genomic understanding of metastatic cSCCs is limited, though VEGFA overexpression has been linked to lymphatic metastasis in mouse models (23).…”

Section: Introductionmentioning

confidence: 99%

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Genomic Analysis of Metastatic Cutaneous Squamous Cell Carcinoma

Hanna

Laga

et al. 2015

Clinical Cancer Research

254

279

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Purpose A rare 5% of cutaneous squamous cell carcinomas metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs. Experimental Design We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy number alterations associated with metastatic cSCC. We determined significantly mutated, deleted and amplified genes and associated genomic alterations with clinical variables. Results The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with HPV. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin. Conclusions We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Genomic Analysis of Metastatic Cutaneous Squamous Cell Carcinoma

Hanna

Laga

et al. 2015

Clinical Cancer Research

254

279

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“…The mouse SCC mutational landscape is similar to that of human SCC We then assessed whether the somatic mutations identified in DMBAinduced msSCC were similar to the mutations found in human SCCs from different body locations such as skin [31][32][33][34] , head and neck 25,35,36 , lung 37 , esophagus 38,39 , mouth 40 , cervix 41 and nasopharynx 42 . Many mouse genes with human counterparts reported to be recurrently mutated in human SCCs from different organs and exposed to different carcinogens, such as Hras, Kras, Trp53, Fat1, Notch1, Notch2, Unc13c, Ash1l, Kmt2d, Kmt2c, Ep300, Setd2, Usp9x, Arid1a, Arid2, Smg1, Nsd1, Nfe2l2, Syne1-2 and Tgfbr2 (refs.…”

Section: Novel Putative Drivers Of Mssccmentioning

confidence: 98%

Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma

Nassar

Latil

Boeckx

et al. 2015

Nat Med

171

162

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Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.

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“…basal cell cancer (Lomas et al, 2012). Exposure to high doses of ultraviolet (UV) light (generally from the sun) can damage the DNA of normal keratinocytes in the epidermis, leading to the development of skin cancer (Lee et al, 2014;Lomas et al, 2012). However, the underlying molecular mechanism(s) responsible for this transition remain obscure, despite ongoing investigations over the past decade.…”

Section: Introductionmentioning

confidence: 99%