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Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma

Abstract

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10−8) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

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Figure 1: Mutational landscape of BCC.
Figure 2: Mutations in copy-neutral LOH regions in BCC.
Figure 3: Functional characterization of N-Myc alterations in BCC.
Figure 4: PTPN14 mutations in BCC.
Figure 5: LATS1 mutations in BCC.
Figure 6: Clonality in sporadic BCCs.
Figure 7: The expression of N-Myc and YAP1 target genes is upregulated in BCC.
Figure 8: Signaling pathways involved in BCC.

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Acknowledgements

We thank Z. Modrusan (next-generation sequencing), R. Piskol (computational biology), G. Pau (computational biology), F. Peale (pathology) and S. Jillo (collaboration management) from Genentech, Inc. This work was supported by Swiss Cancer League (LSCC 2939-02-2012), Dinu Lipatti 2014 and Novartis (14B065) research grants to S.I.N.

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Authors

Contributions

S.I.N. and L.P. designed the project. S.I.N. and X.B. performed high-throughput sequencing data analysis. S.I.N., F.B., K.P., F.A.S. and R.B.C. performed statistical analysis. S.I.N., X.B., H.J.S., F.J.d.S. and S.E.A. wrote the manuscript. V.Z. and O.M. performed in silico modeling. X.B. and P.G.R. performed sample and high-throughput sequencing library preparation. L.P., N.B.-S., G.K. and K.G. collected samples. B.K. and I.A. performed MYCN in vivo experiments. T.M. and C.V. performed PTPN14 immunohistochemistry experiments. S.I.N., A.L. and M. Garieri performed RNA-seq analysis. V.B.S., M.A.A. and S.I.N. performed mutational signature analysis. M. Guipponi, P.G.R. and X.B. performed exome capture and high-throughput sequencing. M.E. and O.S. performed experiments.

Corresponding authors

Correspondence to Stylianos E Antonarakis or Sergey I Nikolaev.

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Integrated supplementary information

Supplementary Figure 1 Mutational signatures in BCC compared to melanoma.

(a) The effect of transcription-coupled repair as a function of gene expression in BCC. Tumor type–specific gene expression levels were used for BCC (this study) and cutaneous melanoma21. Genes were grouped into five equally sized bins by their level of expression. 95% confidence intervals for the ratio between the two binomial distributions were calculated using the R function riskscoreci(). (b) Fraction of each nucleotide 5′ to C>A mutations.

Supplementary Figure 2 Distribution of mutations in BCC driver genes.

(an) Distribution of mutations in the full sample set (293 BCC samples) along the FBXW7 (a), PPP6C (b), STK19 (c), CASP8 (d), RB1 (e), KNSTRN (f), ERBB2 (g), NOTCH2 (h), NOTCH1 (i), ARID1A (j), SMO (k), TP53 (l), PTCH1 (m) and SUFU (n) protein diagrams. The orange lollipops represent truncating mutations, the purple lollipops represent missense mutations and the blue lollipops represent both truncating and missense events affecting the same amino acid. Protein functional domains are represented by colored boxes. The most recurrent events for each protein are labeled with the amino acid change. Protein diagrams were generated with cBioPortal tools.

Supplementary Figure 3 SCNAs in BCC exomes.

Top, overall profile of SCNAs in BCC. LOHs and cnLOHs are on the top (dark blue); amplified regions are on the bottom (red). The positions of relevant genes are marked. Bottom, per-tumor SCNA profile. Each line represents a sample, and each column represents a chromosome. Loss of an allele (LOH) is depicted in blue, cnLOH is indicated in black and copy number gain is indicated in yellow. Chromosomes X and Y have been excluded.

Supplementary Figure 4 LATS2 mutations in BCC.

(a) Distribution of mutations (in the 136 sequenced exomes only) along the LATS2 protein schema. The purple lollipops represent missense mutations, and the orange lollipops represent truncating mutations. Protein functional domains are represented by green boxes. Events occurring two or more times are labeled with the amino acid change. (b) Kinase domain structure of LATS2 highlighting the position of residue Pro1004. The protein diagram was generated with cBioPortal tools.

Supplementary Figure 5 Fraction of tumors with driver mutations per category.

The bars represent the fraction of samples with driver mutations per BCC category indicated in the header (only non-clonal samples were used in this analysis). Vismo, vismodegib. Genes harboring driver mutations are labeled on the x axis. MYCN-p.44 is a subcategory containing only tumors with MYCN p.44 mutations; PTPN14-tr corresponds to PTPN14 truncating mutations. The fraction of tumors represented by the bars can be found at the left.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Note. (PDF 1459 kb)

Supplementary Table 1

Sample characteristics and sequencing statistics. (XLSX 121 kb)

Supplementary Table 2

Cancer panel genes. (XLSX 13 kb)

Supplementary Table 3

Somatic mutations identified in exome and cancer panel sequenced samples. (XLSX 40169 kb)

Supplementary Table 4

Fraction of mutations on the transcribed strand. (XLSX 9 kb)

Supplementary Table 5

MutSigCV analysis of cancer panel genes on exome-sequenced tumors (121 samples). (XLSX 2197 kb)

Supplementary Table 6

TumOnc output for cancer panel genes on the full data set (non-clonal tumors). (XLSX 21 kb)

Supplementary Table 7

Fraction of tumor cells and fraction of UV light–induced mutations per sample. (XLSX 23 kb)

Supplementary Table 8

Somatic copy number aberrations (SCNAs). (XLSX 33 kb)

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Bonilla, X., Parmentier, L., King, B. et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 48, 398–406 (2016). https://doi.org/10.1038/ng.3525

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