Genome instability in human tumorigenesis: microphotometry of interphase nuclei and pathologic mitoses reveals dysplasia.
Tumorigenesis goes with genome instability comprising point mutations and gross chromosome aberrations due to defective DNA repair mechanisms and multiple overrun of cell cycle checkpoints. Pathologic mitoses (CDFs) occur in human precancers and cancers and were detected by nuclear DNAs deviating more or less than 0.5 c from 4.0 c values. Abundant CDFs were recorded above 4.5 c threshold in lesions of the uterine cervix and the stomach. Low-grade dysplasias and well differentiated carcinomas showed 3%-10% CDFs, high-grade dysplasias 30%-44% CDFs in total divisions. Poorly differentiated cancers comprised some 50% CDFs. Most telophase CDFs showed asymmetric morphology and unbalanced DNA content in their corresponding "halves". CDFs precede DNA aneuploidy of interphase nuclei not only in precancers, but also in cancer. Chromatin bridges and lagging chromosomes suggest that unbalanced telophases are caused by somatic nondisjunction. Tumour progression from low-grade to high-grade dysplasia and cancer is characterised by recurrent shifts from 2 c to 4 c interphase nuclei and a remarkable increase in the 5 c exceeding rate. Clonal selection is the gateway in tumorigenesis for aberrant karyotypes.
Steinbeck
R G
RG
Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden. imp1kiel@aol.com
Auer
G U
GU
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology*; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007399:Interphase / Q000502:physiology; D008938:Mitosis / Q000502:physiology*; D009059:Mouth Diseases / Q000235:genetics / Q000473:pathology; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology*; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology*
D004273:DNA, Neoplasm