Intratumor chromosomal heterogeneity in advanced carcinomas of the uterine cervix.
Intratumor heterogeneity in chromosomal aberrations is believed to represent a major challenge in the treatment of cancer. The aim of our work was to assess the chromosomal heterogeneity of advanced cervical carcinomas and to distinguish aberrations that had occurred at a late stage of the disease from early events. A total of 55 biopsies, sampled from 2-4 different sites within 20 tumors, were analyzed by use of comparative genomic hybridization. Heterogeneous aberrations were identified as those present in at least 1 of the biopsies and which were not seen, nor seen as a tendency, in the others of the same tumor. The homogeneous aberrations were those seen in all biopsies of the tumor. The most frequent homogeneous aberrations were gain of 3q (65%), 20q (65%) and 5p (50%), indicating that these are early events in the development of the disease. Chromosomal heterogeneity was observed in 11 tumors. The most frequent heterogeneous aberrations were loss of 4p14-q25 (60% of 10 cases with this aberration), and gain of 2p22-pter (50% of 6 cases), 11qcen-q13 (33% of 9 cases) and 8q (27% of 11 cases), suggesting that these events promote progression at a later stage. Many of the heterogeneous regions contained genes known to influence the prognosis of cervical cancer, such as 7p (EGFR), 8q (c-MYC), 11qcen-q13 (CCND1) and 17q (ERBB2). Three evolution sequences for the subpopulations in the heterogeneous tumors were identified: a serial, a parallel and a mixed sequence. In 2 tumors with a serial sequence, it was indicated that the aberrations +8 and -X had occurred after the other heterogeneous aberrations and hence were the aberrations most recently formed. Our results suggest pronounced chromosomal instability in advanced cervical carcinomas. Moreover, aggressive and treatment-resistant subpopulations may emerge at a late stage and possibly contribute to a poor prognosis of the advanced stages.
Lyng
Heidi
H
Department of Biophysics, The Norwegian Radium Hospital, Oslo, Norway. heidi.lyng@labmed.uio.no
Beigi
Marzieh
M
Svendsrud
Debbie H
DH
Brustugun
Odd T
OT
Stokke
Trond
T
Kristensen
Gunnar B
GB
Sundfør
Kolbein
K
Skjønsberg
Ane
A
De Angelis
Paula M
PM
D001706:Biopsy; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000302:isolation & purification; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology
D004273:DNA, Neoplasm