Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases.
VIN is thought to be the precursor of some VSCCs because it is monoclonal, frequently occurs contiguously with VSCC and shares similar risk factors with a subgroup of VSCC. There has been no conclusive molecular evidence supporting this assumption. We performed X-chromosome inactivation analysis on 9 cases of lone VIN, 10 cases of VSCC and associated contiguous VIN and 11 cases of VSCC and associated noncontiguous VIN. Eight of the 9 cases of lone VIN appeared to be monoclonal. All 7 informative and monoclonal cases of VIN with contiguous VSCC and 6/9 informative cases of VIN with noncontiguous VSCC showed patterns of X-chromosome inactivation consistent with a common monoclonal origin for both VIN and VSCC. Two of the 9 cases of VIN with noncontiguous VSCC showed X-chromosome inactivation patterns consistent with a separate clonal origin. We performed LOH analysis at 6 chromosomal loci on these samples and 7 cases with lymph node metastases. Identical losses occurred 7 times in VIN and contiguous VSCC (random probability 1.2 x 10(-9)), twice in VIN and noncontiguous VSCC (random probability 1.5 x 10(-3)) and 3 times in VSCC and associated metastases (random probability 1.8 x 10(-5)). Some losses occurring in VSCC did not appear in the contiguous VIN or associated metastases and vice versa. These data provide molecular evidence that VIN is the precursor of VIN-associated VSCC, that multifocal disease may arise via either different clones or a single clone and that continued divergent clonal evolution may occur in vulval neoplasia.
Rosenthal
Adam N
AN
Gynaecological Oncology Unit, St. Bartholomew's and Royal London Hospitals Medical College, Queen Mary and Westfield College, Charterhouse Square, London EC1M 6GM, UK.
Ryan
Andy
A
Hopster
Deborah
D
Jacobs
Ian J
IJ
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002875:Chromosomes; D018450:Disease Progression; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D018895:Microsatellite Repeats; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011336:Probability; D014846:Vulvar Neoplasms / Q000235:genetics* / Q000378:metabolism; D014960:X Chromosome