Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.
OBJECTIVE
BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC.


METHODS
Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology.


RESULTS
Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected.


CONCLUSIONS
We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general.
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. cohen.daniel@mayo.edu.
Daniel N
DN
Cohen
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Steven K
SK
Lawson
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Aaron C
AC
Shaver
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Liping
L
Du
University of Texas, Department of Dermatology, Houston, Texas.
Harrison P
HP
Nguyen
University of Texas, Department of Dermatology, Houston, Texas.
Qin
Q
He
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Douglas B
DB
Johnson
Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee.
Wilfred A
WA
Lumbang
Heritage Medical Associates, Nashville, Tennessee.
Brent R
BR
Moody
PathGroup, Nashville, Tennessee.
James L
JL
Prescott
PathGroup, Nashville, Tennessee.
Pranil K
PK
Chandra
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee. Pathology Consultants of America, Columbia, Tennessee.
Alan S
AS
Boyd
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee.
Jeffrey P
JP
Zwerner
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee. Pathology Associates of St. Thomas, Nashville, Tennessee.
Jason B
JB
Robbins
University of Texas, Department of Dermatology, Houston, Texas.
Stephen K
SK
Tyring
University of Texas, Department of Dermatology, Houston, Texas.
Peter L
PL
Rady
Departments of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
James D
JD
Chappell
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Yu
Y
Shyr
Sarah Cannon Research Institute, Nashville, Tennessee.
Jeffrey R
JR
Infante
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.
Jeffrey A
JA
Sosman
D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics* / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000821:virology; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000150:complications / Q000235:genetics* / Q000503:physiopathology / Q000821:virology; D013449:Sulfonamides / Q000008:administration & dosage; D014466:Ultraviolet Rays; D000077484:Vemurafenib
D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf