Field cancerization: why late "recurrent" ovarian cancer is not recurrent.
OBJECTIVE
Late "recurrence" of ovarian cancer may result from either regrowth of dormant tumor cells or from development of a new cancer caused by the phenomenon of field cancerization. Clinically, some recurrent ovarian cancers show the same therapeutic sensitivities to chemotherapy and surgery as did the primary disease, whereas others are refractory to all therapy. We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer.


METHODS
We constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats.


RESULTS
The average age at initial diagnosis for this cohort was 54.7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells.


CONCLUSIONS
Our results are consistent with the "field cancerization" hypothesis of ovarian carcinogenesis but could also be explained by a polyclonal tumor origin, which contrasts with the currently accepted monoclonal theory of ovarian carcinogenesis. Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer.
Buller
R E
RE
Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City, USA.
Skilling
J S
JS
Sood
A K
AK
Plaxe
S
S
Baergen
R N
RN
Lager
D J
DJ
D000368:Aged; D018283:Cystadenocarcinoma, Papillary / Q000235:genetics; D016172:DNA Fingerprinting; D004303:Dosage Compensation, Genetic; D005260:Female; D016158:Genes, p53; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
D005819:Genetic Markers