AbstractLittle is known about the genomic abnormalities of squamous cell carcinomas (SCC) of the vulva and how they correlate with gene expression. We determined the genomic and expression profiles of 15 such SCC using karyotyping, DNA ploidy analysis, arrayCGH, and expression arrays. Four of the five cases with clonal chromosomal aberrations found by G‐banding showed highly abnormal karyotypes with multiple rearrangements. The imbalances scored by arrayCGH mapped to different chromosomes with losses being more common than gains. Frequent losses were scored from 3p and 8p whereas gains were frequent from 3q and 8q (loss of 8p with concomitant gain of 8q mostly occurred via 8q isochromosome formation). This is the first study of vulvar tumors using arrayCGH, and some frequent imbalances could be defined precisely. Of particular note were the sometimes large, sometimes small deletions of 3p and 9p which had minute areas in 3p14 and 9p23 as minimal commonly deleted regions. FHIT (3p14) and PTPRD (9p23) are the only genes here. They were both lost in seven cases, including homozygous losses of PTPRD in four tumors. Using qPCR we could demonstrate deregulation of the FHIT gene in tumor cells. Hence, this gene is likely to play a pathogenetic role in vulvar SCC tumorigenesis. Expression array analyses also identified a number of other genes whose expression profile was altered. Notable among the downregulated genes were MAL (in 2q11), KRT4 (in 12q13), and OLFM4 (in 13q14), whereas upregulated genes included SPRR2G (in 1q21.3) and S100A7A (in 1q21.3). © 2013 Wiley Periodicals, Inc.