Molecular testing in metastatic basal cell carcinoma

Babette J A Verkouteren; Marlies Wakkee; Michel van Geel; Remco van Doorn; Véronique J Winnepenninckx; Esther Korpershoek; Antien L Mooyaart; An K L Reyners; Jorrit B Terra; Maureen J B Aarts; Marie G H C Reinders; Klara Mosterd

doi:10.1016/j.jaad.2019.12.026

Molecular testing in metastatic basal cell carcinoma

Babette J A Verkouteren^*
, Marlies Wakkee
, Michel van Geel
, Remco van Doorn
, Véronique J Winnepenninckx
, Esther Korpershoek
, Antien L Mooyaart
, An K L Reyners
, Jorrit B Terra
, Maureen J B Aarts
, Marie G H C Reinders
, Klara Mosterd

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1135-1142
Number of pages	8
Journal	Journal of the American Academy of Dermatology
Volume	85
Issue number	5
Early online date	21 Dec 2019
DOIs	https://doi.org/10.1016/j.jaad.2019.12.026
Publication status	Published - Nov 2021

Keywords

basal cell carcinoma
hedgehog pathway
metastatic
molecular genetics
targeted therapy
vismodegib
GENOMIC ANALYSIS
VISMODEGIB
RESISTANCE

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Verkouteren, B. J. A., Wakkee, M., van Geel, M., van Doorn, R., Winnepenninckx, V. J., Korpershoek, E., Mooyaart, A. L., Reyners, A. K. L., Terra, J. B., Aarts, M. J. B., Reinders, M. G. H. C., & Mosterd, K. (2021). Molecular testing in metastatic basal cell carcinoma. Journal of the American Academy of Dermatology, 85(5), 1135-1142. https://doi.org/10.1016/j.jaad.2019.12.026

@article{1ea464165fef41359d364d73ec42e968,

title = "Molecular testing in metastatic basal cell carcinoma",

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.",

keywords = "basal cell carcinoma, hedgehog pathway, metastatic, molecular genetics, targeted therapy, vismodegib, GENOMIC ANALYSIS, VISMODEGIB, RESISTANCE",

author = "Verkouteren, \{Babette J A\} and Marlies Wakkee and \{van Geel\}, Michel and \{van Doorn\}, Remco and Winnepenninckx, \{V{\'e}ronique J\} and Esther Korpershoek and Mooyaart, \{Antien L\} and Reyners, \{An K L\} and Terra, \{Jorrit B\} and Aarts, \{Maureen J B\} and Reinders, \{Marie G H C\} and Klara Mosterd",

year = "2021",

month = nov,

doi = "10.1016/j.jaad.2019.12.026",

language = "English",

volume = "85",

pages = "1135--1142",

journal = "Journal of the American Academy of Dermatology",

issn = "0190-9622",

publisher = "Elsevier Inc.",

number = "5",

}

TY - JOUR

T1 - Molecular testing in metastatic basal cell carcinoma

AU - Verkouteren, Babette J A

AU - Wakkee, Marlies

AU - van Geel, Michel

AU - van Doorn, Remco

AU - Winnepenninckx, Véronique J

AU - Korpershoek, Esther

AU - Mooyaart, Antien L

AU - Reyners, An K L

AU - Terra, Jorrit B

AU - Aarts, Maureen J B

AU - Reinders, Marie G H C

AU - Mosterd, Klara

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - basal cell carcinoma

KW - hedgehog pathway

KW - metastatic

KW - molecular genetics

KW - targeted therapy

KW - vismodegib

KW - GENOMIC ANALYSIS

KW - VISMODEGIB

KW - RESISTANCE

U2 - 10.1016/j.jaad.2019.12.026

DO - 10.1016/j.jaad.2019.12.026

M3 - Article

C2 - 31870915

SN - 0190-9622

VL - 85

SP - 1135

EP - 1142

JO - Journal of the American Academy of Dermatology

JF - Journal of the American Academy of Dermatology

IS - 5

ER -

Molecular testing in metastatic basal cell carcinoma

Abstract

Keywords

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