Molecular testing in metastatic basal cell carcinoma - 24/02/20

Doi : 10.1016/j.jaad.2019.12.026

Babette J.A. Verkouteren, MD ^a,^b,^⁎ , Marlies Wakkee, MD, PhD ^c, Michel van Geel, PhD ^a,^b,^d, Remco van Doorn, MD, PhD ^e, Véronique J. Winnepenninckx, MD, PhD ^f, Esther Korpershoek, PhD ^g, Antien L. Mooyaart, MD, PhD ^g, An K.L. Reyners, MD, PhD ^h, Jorrit B. Terra, MD, PhD ⁱ, Maureen J.B. Aarts, MD, PhD ^b,^j, Marie G.H.C. Reinders, MD, PhD ^a,^b, Klara Mosterd, MD, PhD ^a,^b
^a Department of Dermatology, Maastricht University Medical Center, Maastricht, the Netherlands
^b GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
^c Department of Dermatology, Erasmus University Medical Center Cancer Institute, Rotterdam, the Netherlands
^d Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
^e Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
^f Department of Pathology, Maastricht University Medical Center, Maastricht, the Netherlands
^g Department of Pathology, Erasmus University Medical Center Cancer Institute, the Netherlands
^h Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
ⁱ Department of Dermatology, Isala Dermatologic Center, Zwolle, the Netherlands
^j Department of Medical Oncology, Maastricht University Medical Center, Maastricht, the Netherlands

^∗Correspondence and reprint requests to: Babette J. A. Verkouteren, MD, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands.P. Debyelaan 25Maastricht6229 HXthe Netherlands

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Abstract

Background

Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor.

Objective

To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC.

Methods

Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter.

Results

In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib.

Limitations

In 2 patients there was insufficient qualitative DNA available for genetic analysis.

Conclusions

Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value.

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Key words : basal cell carcinoma, hedgehog pathway, metastatic, molecular genetics, targeted therapy, vismodegib

Abbreviations used : BCC, Erasmus MC, FFPE, Maastricht UMC+, mBCC, NCBI, NGS, smMIP

Plan

	Funding sources: None.
	Conflicts of interest: Dr Aarts has advisory relationships with BMS. Drs Verkouteren, Wakkee, van Geel, van Doorn, Winnepenninckx, Korpershoek, Mooyaart, Reyners, Terra, Reinders, and Mosterd have no conflict of interest to declare.
	IRB approval status: Reviewed and approved by the Maastricht University Medical Center+ Ethics Committee (#15-4-231).