Chromosomal Heteromorphisms and Cancer Susceptibility Revisited

Abstract

Chromosomal heteromorphisms (CHs) are a part of genetic variation in man. The past literature largely posited whether CHs could be correlated with the development of malignancies. While this possibility seemed closed by end of the 1990s, recent data have raised the question again on the potential influences of repetitive DNA elements, the main components of CHs, in cancer susceptibility. Such new evidence for a potential role of CHs in cancer can be found in the following observations: (i) amplification and/or epigenetic alterations of CHs are routinely reported in tumors; (ii) the expression of CH-derived RNA in embryonal and other cells under stress, including cancer cells; (iii) the expression of parts of CH-DNA as long noncoding RNAs; plus (iv) theories that suggest a possible application of the “two-hit model” for euchromatic copy number variants (CNVs). Herein, these points are discussed in detail, which leads to the conclusion that CHs are by far not given sufficient consideration in routine cytogenetic analysis, e.g., leukemias and lymphomas, and need more attention in future research settings including solid tumors. This heightened focus may only be achieved by approaches other than standard sequencing or chromosomal microarrays, as these techniques are at a minimum impaired in their ability to detect, if not blind to, (highly) repetitive DNA sequences.

Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines

“…However, despite significant advances in this area, we still do not know much about the structure and functions of these amazing sequences. One of the main obstacles to the study of the functions of tandemly repeated satellite DNA was the lack of a complete map of the chromosome pericentromeric regions [ 20 ]. Until 2022, HSAT1–3 arrays in the human genome were not mapped precisely with their approximate locations in the genome assembly marked as enormous gaps filled with placeholder “N” characters [ 7 ].…”

“…Despite the initial ideas about transcriptionally silent pericentromeres, we know now that the DNA of all HSAT families (HSAT1-3) can be transcribed in a cell under certain circumstances (stress, malignization, cancer-associated polarization, differentiation, senescence, oogenesis, and embryogenesis) [ 19 , 25 , 41 , 42 , 43 ]. In cancer cells, HSAT DNA and RNA contribute to genetic instability [ 20 , 44 , 45 , 46 , 47 ]. In tumors as a whole, pericentromeric transcripts transcribed in microenvironment cells (e.g., fibroblasts) can increase drug resistance, provoke inflammation, activate the innate immune system, etc.…”

“…Earlier, we detected HS2/HS3 transcription in human preovulatory oocytes [ 17 , 18 ], some cancer cell lines, and senescent and cancer-associated fibroblasts [ 13 , 19 ]. At that time, mapping the sequence onto human chromosomes and analysis of adjacent chromosomal regions was complicated because pericentromeric and centromeric TR DNA sequences remained almost entirely missing from the assembled human reference genome for the past 20 years [ 20 ]. The majority of these sequences were also not annotated.…”

“…The absence of pericentromeric region maps [ 20 ] made it difficult to study the functions of the long noncoding RNA (lncRNA) transcribed from pericentromeres. The publication of the gapless T2T-CHM13 assembly allowed us to continue our study of the HS2/HS3 transcription.…”