PubMed · 6578653
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G Giacomini, U Simi. CIN or not CIN.. https://pubmed.ncbi.nlm.nih.gov/6578653/
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Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.
Throughout the last century, aneuploidy has been cemented as a hallmark of cancer. Although the association of aneuploidy with tumorigenesis has been well established, the role of these genetic imbalances in tumor formation has only recently begun to be elucidated. Advancements in genomics have revealed the complexity and context dependence of the effect of aneuploidy on cancer growth, while developments in genetic editing have allowed for proper modeling of specific aneuploidies. In this review, we discuss the key factors to consider when studying the role of aneuploidy in cancer and the tools that are available to do so. We then highlight recent studies that establish phenotypic contributions of aneuploidy to tumorigenicity. In particular, we highlight how general aneuploidy and chromosomal instability affect the tumor microenvironment and how specific chromosomal alterations, including the loss of chromosome 9p and the gain of chromosomes 8q and 1q, influence tumor behavior and therapeutic responses. Finally, we emphasize the potential of targeting aneuploidy-induced vulnerabilities to improve cancer treatment outcomes.
Comparative genomic hybridization serves as a screening test for regions of copy number changes in tumor genomes. We have applied the technique to map DNA gains and losses in 33 cases of formalin-fixed, paraffin-embedded primary breast tumors (13 fibroadenomas and 10 diploid and 10 aneuploid carcinomas). No genomic imbalances were found in fibroadenomas. Recurrent findings in adenocarcinomas include copy number increases for chromosomes 1q (14 of 20 samples), 8q (10 of 20), 17q (5 of 20), 6p (3 of 20), 13q (3 of 20), and 16p (3 of 20), and copy number decreases for chromosomes 22 (7 of 20), 17p (6 of 20), and 20 (3 of 20). Regional high level copy number increases were observed on chromosome bands 1q32, 8p11, 8q24, 10p, 11q13, 12p, 12q15, 17q11-12, and 17q22-24. The majority of the samples were studied for gene amplification of c-myc, c-erbB2, cycD1, and int-2 by means of Southern blot analysis. The comparison with DNA ploidy measurements revealed a different distribution and a significantly higher number of chromosomal aberrations in aneuploid tumors than in diploid tumors and in fibroadenomas.