Low incidence of EGFR and HRAS mutations in cutaneous squamous cell carcinomas of a German cohort

Abstract

Epidermal growth factor receptor (EGFR) is highly expressed in squamous cell carcinoma (SCC). The response of patients with lung cancer to EGFR inhibitors is significantly associated with the presence of EGFR mutations. Although these drugs have already been used for the treatment of advanced cutaneous SCC, the knowledge about EGFR mutations in this cancer is limited to one previous study in the US population. We analysed the presence of EGFR and concomitant HRAS mutations in a German cohort of 31 patients with cutaneous SCC by direct sequencing of EGFR and SNaPshot analysis of concomitant RAS mutations. We found a low prevalence of EGFR mutations (1 ⁄ 31; 3%) and HRAS mutations (1 ⁄ 31; 3%). The detected P741L EGFR mutation was proven to be somatic. Our results indicate that both EGFR and HRAS mutations are rare events in the carcinogenesis of cutaneous SCC, and therefore, only a small subgroup of patients will benefit from the screening for EGFR mutations in the run-up to targeted therapies with EGFR inhibitors.

Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas

“…The only problem that arises is the variable frequency of ras mutations in NMSC, which, in certain previous studies, has reached 22% (24)(25)(26).…”

“…This last step often leads to resistance to EGFR inhibitor drugs, including cetuximab, panitumumab, gefitinib and erlotinib. The percentage of ras mutations in NMSC widely varies: The values reported in clinical studies can range from 2 to 22% (24)(25)(26).…”

Mosaic RASopathies

“…This view is supported by the fact that RAS mutations are associated with keratoacanthomas and squamous cell carcinomas that develop in patients with metastasized malignant melanomas receiving a therapy with a BRAF inhibitor. While the prevalence of RAS mutations in sporadic human squamous cell carcinomas is rather low, 68 RAS mutations are significantly more frequent in these tumors developing under BRAF inhibitor therapy. 69 These findings suggest a model of tumor growth by paradoxical pathway activation by BRAF inhibitors in RAS-primed mutant keratinocytes.…”

Modeling Cutaneous Squamous Carcinoma Development in the Mouse

“…Recent somatic mutation analyses of sporadic skin SCCs have revealed frequent mutations in NOTCH1, NOTCH2, TP53, CDKN2A, HRAS, and KRAS (Durinck et al 2011;Mauerer et al 2011;Wang et al 2011). These new studies emphasize the strong similarities between the mutation spectra in human squamous tumors at different sites including the skin, head and neck, and lung (Agrawal et al 2011;Stransky et al 2011;The Cancer Genome Atlas Research Network 2012).…”

“…For instance, while RAS mutations are seen in 3% -25% of human SCC cases (Khavari 2006;Durinck et al 2011;Mauerer et al 2011), they are extremely rare in this model (van Kranen et al 1995). Work in this area is hampered by the fact that SKH-1 mice have a nonfunctional Hairless (Hr) gene, and although this confers a practical advantage for experiments involving controlled exposure to UV light on a daily basis, the Hr gene plays an important role in skin metabolism (Kumpf et al 2012), and its absence may influence the pathways by which tumors develop in this model.…”