1.

Introduction

The field of cancer genetics focuses on the processes by which a somatic cell can change
through internal DNA changes, epigenetic changes, structural chromosomal aberrations, and
numerical chromosomal changes. Although it is debated how a cell develops into
malignancy, it has been proposed that, in addition to normal mutations and the possible
clonal spread of these mutations, three important sources of error can affect genomic stability
in human cancer: nucleotide excision repair instability (NIN). microsatellite instability
(MIN), and chromosomal instability (CIN). Loeb and colleagues collectively call these
expressions the "mutator phenotype," in which a mutation in any gene responsible for
maintaining DNA integrity through replication, repair, chromosome segregation, damage
surveillance, or apoptosis can cause human formation and progression. tumors (Loeb et al.,
2003). While NIN and MIN are the primary defects in rare or hereditary cancers that contain
mutations in DNA damage repair genes, CIN occurs in cancers that do not contain nucleotide
or microsatellite instability (Lengauer et al., 1998). Gisselsson recently reviewed several
factors that have been shown to induce, maintain, and repair CIN (Gisselsson, 2003). Due to
the complex nature of CIN, the mechanism(s) by which factors individually and collectively
contribute to this cancer phenomenon remain to be elucidated (Figure).

Chromosomal instability (CIN) plays a significant role in the development and progression of
various cancers, including squamous cell carcinoma (SCC) of the oral cavity. SCC is the
most common type of oral cancer, accounting for the majority of cases worldwide. The oral
cavity, comprising the lips, tongue, gingiva, floor of the mouth, palate, and the inner lining of
the cheeks, is susceptible to the carcinogenic effects of environmental factors such as tobacco
use, alcohol consumption, and human papillomavirus (HPV) infection.

CIN refers to the increased rate of gain or loss of whole chromosomes or large segments of
chromosomes within cancer cells. This genomic instability leads to heterogeneous
populations of tumor cells with varying genetic compositions, contributing to tumor
heterogeneity and evolution. In oral SCC, CIN is associated with tumor initiation,
progression, metastasis, and resistance to therapy.

Squamous cell carcinoma (SCC) of the oral cavity represents a significant burden on global
health, with its incidence steadily rising across various populations. Understanding the
molecular mechanisms underlying the development and progression of oral SCC is crucial
for improving diagnostic and therapeutic strategies. Among the emerging hallmarks of
cancer, chromosomal instability (CIN) has garnered substantial attention for its role in
tumorigenesis and disease heterogeneity. In oral SCC, CIN manifests as aberrations in
chromosomal structure and number, contributing to tumor initiation, progression, and
therapeutic resistance. This critical review aims to provide a comprehensive overview of
chromosomal instability in oral SCC, elucidating its molecular underpinnings, clinical
implications, and potential therapeutic targets.

1
Early studies by Rosin et al. (2000) demonstrated the predictive value of allelic loss patterns
in low-grade oral epithelial dysplasia, highlighting the importance of genetic alterations in
early cancer detection. Subsequent investigations by Califano et al. (2003) proposed a genetic
progression model for head and neck cancer, shedding light on the clonal evolution of pre-
neoplastic lesions and the acquisition of additional genetic alterations during tumor
progression. These seminal works laid the foundation for understanding the molecular
landscape of oral SCC and its association with chromosomal instability.

Several studies have highlighted the prevalence and clinical significance of CIN in oral SCC.
For example, a study by Lui et al. (2017) demonstrated a correlation between CIN and
aggressive clinicopathological features, such as advanced tumor stage, lymph node
metastasis, and poor prognosis in oral SCC patients. Additionally, genomic profiling studies
have identified recurrent chromosomal aberrations, including gains, losses, and
translocations, in oral SCC tumors, further underscoring the role of CIN in driving
tumorigenesis and disease progression.

Recent advances in genomic technologies have further deepened our understanding of CIN in
oral SCC. Studies by Li et al. (2021) have leveraged multi-omics analysis to delineate the
genomic, epigenomic, and proteomic alterations driving oral SCC tumorigenesis.
Additionally, Zheng et al. (2020) have employed single-cell sequencing and spatial
transcriptomics to dissect intra-tumoral heterogeneity and identify clonal evolution dynamics
within tumors.

Squamous cell carcinoma of the head and neck (SCCHN) and its subset, oral squamous cell
carcinoma (OSCC), arise through an accumulation of genetic alterations, including
chromosomal alterations, DNA changes (e.g., mutations, amplifications, or deletions), and/or
epigenetic alterations, such as changes in methylation that affect genetic regulation. These
events are further influenced by exposure to environmental agents, including tobacco smoke,
alcoholic beverages, and viruses, such as human papillomavirus (Forastiere et al., 2001;
Mork et al., 2001). Previous studies have demonstrated that karyotypes of SCCHN and
OSCC consist of near-triploid chromosome numbers and contain various patterns of
cytogenetic aberrations, including structural and numerical chromosome abnormalities
(Gollin, 2001; Jin et al., 2002). These include, but are not limited to: aneuploidy (gains or
losses of whole chromosomes, resulting in a chromosome number altered from that of diploid
cells, but which may or may not affect ploidy status [Åkervall et al., 1998]); translocations
(balanced or unbalanced re-arrangement of chromosome segments or entire chromosome
arms); insertions (breaks either within a chromosome or between two chromosomes,
resulting in the direct addition of chromosomal material or, alternatively, the addition of
material in the opposite, inverted direction); deletions (loss of small or large DNA segments);
and amplifications (multiple additional copies of a specific gene or chromosomal region in
the form of extrachromosomal double minutes [dmin] or intrachromosomal homogeneously
staining regions [hsrs])

2
Figure: The origins of chromosomal

Recent studies have described the presence of mitotic dysfunction in tumor cells, including
aberrant centrosome numbers, anaphase bridges, multipolar mitotic divisions and dysfunctional
telomeres (Saunders et al., 2000; Gisselsson et al., 2002; Gisselsson, 2003). The following is an
overview of our current knowledge of factors associated with chromosomal instability,
particularly in oral cancer.

2. Background/Historical Context

The historical context of chromosomal instability (CIN) in squamous cell carcinoma (SCC) of
the oral cavity, early studies provided foundational insights into the genetic alterations
underlying oral SCC tumorigenesis. For instance, research by Rosin et al. (2000) demonstrated
the predictive value of allelic loss patterns in low-grade oral epithelial dysplasia for identifying
malignant risk. This seminal work underscored the importance of genetic alterations in the early
stages of oral cancer development. Furthermore, studies by Mao et al. (1996) and Califano et al.

3
(1996) identified specific chromosomal regions frequently affected by allelic loss in oral SCC,
providing valuable information on potential tumor suppressor gene loci and pathways involved
in oral cancer pathogenesis.

Chromosomal instability (CIN) has long been recognized as a hallmark of cancer, including
squamous cell carcinoma (SCC) in the oral cavity. The oral cavity is particularly susceptible to
the effects of carcinogens due to its direct exposure to environmental factors such as tobacco
smoke, alcohol consumption, and viral infections like human papillomavirus (HPV). These
carcinogens can induce genetic alterations that contribute to the initiation and progression of oral
SCC.

Advances in molecular cytogenetics and genomic profiling techniques have facilitated a deeper
understanding of the genetic landscape of oral SCC. For instance, comparative genomic
hybridization (CGH) studies have identified specific chromosomal regions that are frequently
amplified or deleted in oral SCC, highlighting the heterogeneity and complexity of genomic
alterations driving tumorigenesis.

Historically, squamous cell carcinoma (SCC) of the oral cavity has been primarily understood
through histopathological examination and clinical observations. However, advancements in
molecular biology have shed light on the underlying genetic alterations driving this malignancy,
particularly the phenomenon of chromosomal instability (CIN) (Rosin et al., 2000). Early studies
by Rosin and colleagues (2000) provided seminal insights into the genomic alterations associated
with oral SCC, demonstrating the presence of chromosomal aberrations in tumor tissues.

The discovery of CIN in oral SCC marked a paradigm shift in understanding the molecular
mechanisms underpinning tumorigenesis and tumor progression. These findings paved the way
for further investigations into the role of CIN in oral cancer, aiming to elucidate its impact on
disease development and clinical outcomes. Subsequent studies by Califano et al. (2003)
corroborated and expanded upon these initial observations, highlighting the diverse array of
chromosomal alterations present in oral SCC tumors.

The historical context of oral SCC research also encompasses advancements in diagnostic
technologies and preventive strategies. Visualization techniques, such as autofluorescence
imaging and narrow-band imaging, have emerged as valuable tools for early detection and
surveillance of oral potentially malignant disorders (Rosin et al., 2005). Additionally, efforts to
identify biomarkers for risk stratification and prognostic assessment have contributed to the
development of molecular diagnostic assays and predictive models.

The exploration of field cancerization in head and neck cancer further elucidated the molecular
landscape of oral SCC. Califano et al. (2003) proposed a genetic progression model, highlighting
the clonal evolution of pre-neoplastic lesions and the acquisition of additional genetic alterations
during tumor progression. This model provided a framework for understanding the molecular

4
heterogeneity and multifocal nature of oral SCC, laying the groundwork for subsequent studies
on CIN.

The historical context of oral SCC research encompasses the exploration of various genetic and
environmental factors contributing to tumor initiation and progression. Studies have implicated
tobacco use, alcohol consumption, viral infections (e.g., human papillomavirus), and genetic
predispositions in the etiology of oral SCC (Rosin et al., 2000; Thomas et al., 2004).
Investigations into the genetic basis of oral SCC have revealed associations between cytokine
gene polymorphisms and disease susceptibility (Thomas et al., 2004). Studies have identified
genetic variants in interleukin and tumor necrosis factor genes implicated in immune regulation
and inflammation, providing insights into the interplay between genetic factors and
environmental exposures in oral cancer pathogenesis.

The historical background of oral SCC research underscores the evolving understanding of the
molecular landscape of this malignancy, with CIN emerging as a key determinant of tumor
behavior and clinical outcomes. These early insights laid the foundation for subsequent
investigations into the diagnostic and prognostic implications of chromosomal instability in oral
SCC, shaping contemporary approaches to cancer management and personalized medicine.

3. Current Perspectives

Contemporary perspectives on chromosomal instability (CIN) in squamous cell carcinoma (SCC)

of the oral cavity delve into the intricate molecular mechanisms underlying tumorigenesis and
tumor progression, offering valuable insights into diagnostic and prognostic implications. Recent
research endeavors have focused on elucidating the heterogeneous nature of CIN patterns across
oral SCC tumors and their correlation with clinicopathological characteristics (Martincorena et
al., 2017). Advances in genomic profiling techniques, such as next-generation sequencing (NGS)
and array comparative genomic hybridization (aCGH), have facilitated comprehensive analyses
of chromosomal alterations in oral SCC, revealing complex genomic landscapes characterized by
chromosomal gains, losses, and rearrangements (Yoo et al., 2020; Agrawal et al., 2012).

Contemporary studies have highlighted the clinical significance of CIN in oral SCC, with
implications for patient stratification and treatment selection. Tumors exhibiting high levels of
chromosomal instability may represent a distinct molecular subtype associated with aggressive
disease behavior and poor prognosis (Martincorena et al., 2017; Curtin et al., 2005). Conversely,
tumors with low CIN levels may exhibit a more indolent course and better treatment response,
underscoring the potential utility of CIN biomarkers in guiding therapeutic decisions (Yoo et al.,
2020; Garnett et al., 2002).

To its prognostic implications, CIN in oral SCC has been implicated in therapeutic resistance and
disease recurrence. Tumors with elevated levels of chromosomal instability may harbor genetic

5
alterations conferring resistance to standard treatment modalities, such as chemotherapy and
radiation therapy (Yoo et al., 2020; Sun et al., 2019). Therefore, understanding the molecular
mechanisms driving CIN and its impact on treatment response is essential for developing
targeted therapeutic strategies tailored to individual patient profiles.

Emerging evidence suggests a potential role for CIN biomarkers in predicting treatment response
and monitoring disease progression in oral SCC patients. Molecular profiling of tumor tissues
and liquid biopsies (e.g., circulating tumor DNA) may offer non-invasive means of assessing
CIN status and monitoring treatment efficacy over time (Martincorena et al., 2017; Qiu et al.,
2021). Integration of CIN biomarkers into clinical practice holds promise for enhancing
diagnostic accuracy, prognostic assessment, and treatment optimization in oral SCC.

Current perspectives on chromosomal instability in oral SCC underscore its multifaceted role in
tumor biology and clinical management. By unraveling the complexities of CIN and its
implications for diagnosis and prognosis, ongoing research efforts aim to improve patient
outcomes and advance personalized cancer care strategies.

4. Future perspectives

Future perspectives on chromosomal instability (CIN) in squamous cell carcinoma (SCC) of

the oral cavity hold promise for advancing diagnostic and prognostic approaches, as well as
guiding personalized therapeutic interventions. One avenue for future research involves
elucidating the molecular mechanisms underlying CIN in oral SCC and its interplay with
tumor microenvironment components, such as immune cells and stromal elements (Burrell et
al., 2013). By comprehensively characterizing the genetic and epigenetic alterations driving
chromosomal instability, researchers can identify novel therapeutic targets and biomarkers
for patient stratification and treatment response prediction.

Future studies may explore the utility of emerging technologies, such as single-cell
sequencing and spatial transcriptomics, in dissecting intra-tumoral heterogeneity and spatial
distribution of chromosomal alterations in oral SCC tumors (Zheng et al., 2020). High-
resolution genomic profiling at the single-cell level can provide insights into clonal evolution
dynamics and lineage relationships within tumors, facilitating the identification of driver
events driving tumor progression and therapeutic resistance.

In addition to molecular profiling approaches, future research endeavors may focus on

integrating multi-omics data (e.g., genomics, transcriptomics, proteomics) to generate
comprehensive molecular portraits of oral SCC tumors (Li et al., 2021). By integrating
diverse molecular datasets, researchers can gain a holistic understanding of the complex
biological processes underlying tumorigenesis and identify actionable targets for therapeutic
intervention.

6
The advent of precision medicine approaches offers exciting prospects for tailoring
therapeutic strategies to the individual molecular profiles of oral SCC patients (Burrell et al.,
2013). Targeted therapies directed against specific genetic alterations driving chromosomal
instability, such as DNA repair pathway defects or oncogenic driver mutations, may improve
treatment efficacy and minimize off-target effects. Additionally, the development of
predictive biomarkers for treatment response and resistance will be essential for optimizing
patient outcomes and minimizing therapeutic failures.

Future research efforts may explore the potential of immunotherapeutic approaches, such as
immune checkpoint inhibitors, in harnessing the host immune system to target CIN-driven
oral SCC tumors (Zheng et al., 2020). By leveraging the immune-modulatory properties of
CIN-associated antigens, researchers can develop novel immunotherapeutic strategies aimed
at enhancing anti-tumor immune responses and overcoming immune evasion mechanisms
employed by tumor cells.

Several areas warrant further investigation to address key challenges and capitalize on
emerging opportunities.

Identification of Driver Genes: Despite the identification of recurrent chromosomal

aberrations in oral SCC, the specific driver genes within these regions remain largely
unknown. Future studies employing high-throughput sequencing technologies, such as
whole-genome sequencing and single-cell sequencing, hold the potential to uncover novel
driver mutations and oncogenic pathways driving CIN in oral SCC.

Functional Characterization of CIN: Understanding the functional consequences of

chromosomal alterations in oral SCC is essential for elucidating their role in tumor initiation,
progression, and therapeutic response. Integrative approaches combining genomic profiling
with functional genomics techniques, such as CRISPR/Cas9-mediated gene editing and
functional RNA interference (RNAi) screens, can help delineate the biological significance
of CIN-associated genes and pathways.

Therapeutic Targeting of CIN: Exploiting vulnerabilities associated with CIN in oral SCC
represents a promising avenue for the development of targeted therapies. Future studies
focused on identifying synthetic lethal interactions and druggable targets specifically
associated with chromosomally unstable tumors may lead to the discovery of novel
therapeutic strategies tailored to individual patients based on their genomic profiles.

Precision Medicine Approaches: The integration of genomic information, including CIN

status, into clinical decision-making holds potential for optimizing treatment selection and
improving patient outcomes. Future clinical trials incorporating genomic biomarkers, such as
chromosomal aberrations and mutational signatures associated with CIN, can facilitate the
development of personalized therapeutic regimens for patients with oral SCC.

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 Biomarker Development and Clinical Validation: Robust biomarkers of CIN in oral SCC
are needed to guide prognosis, predict treatment response, and monitor disease progression.
Future research efforts should focus on the validation of candidate biomarkers through large-
scale clinical studies and the development of non-invasive diagnostic assays for routine
clinical use.

5. Conclusion

The critical review of chromosomal instability (CIN) in squamous cell carcinoma (SCC) of the
oral cavity highlights its multifaceted implications for cancer diagnosis, prognosis, and
therapeutic strategies. The elucidation of the molecular mechanisms driving CIN has advanced
our understanding of oral SCC pathogenesis and provided valuable insights into its clinical
behavior and treatment outcomes.

Through comprehensive genomic profiling and molecular characterization, researchers have

identified distinct patterns of chromosomal alterations associated with oral SCC tumors, offering
potential biomarkers for diagnostic and prognostic assessment (Martincorena et al., 2017). High
levels of CIN may serve as indicators of aggressive disease behavior and poor prognosis, guiding
clinicians in risk stratification and treatment decision-making (Yoo et al., 2020). Conversely,
tumors with low CIN levels may exhibit a more favorable clinical course and treatment response,
offering opportunities for tailored therapeutic interventions.

The integration of CIN biomarkers into clinical practice holds promise for enhancing diagnostic
accuracy and prognostic assessment in oral SCC patients. Molecular profiling techniques, such
as next-generation sequencing and array comparative genomic hybridization, enable the
identification of actionable genetic alterations driving tumorigenesis and therapeutic resistance
(Burrell et al., 2013). By leveraging these insights, clinicians can optimize treatment strategies
and improve patient outcomes through personalized medicine approaches.

Future research endeavors may explore the potential of immunotherapeutic strategies in targeting
CIN-driven oral SCC tumors (Zheng et al., 2020). Immune checkpoint inhibitors and other
immunomodulatory agents offer novel avenues for enhancing anti-tumor immune responses and
overcoming immune evasion mechanisms employed by tumor cells. By harnessing the host
immune system, researchers can develop innovative therapeutic approaches that complement
traditional treatment modalities and improve long-term survival outcomes.

The critical review underscores the pivotal role of chromosomal instability in shaping the clinical
behavior and management of squamous cell carcinoma in the oral cavity. By unraveling the
complexities of CIN-driven tumorigenesis and leveraging molecular insights, we can advance
personalized cancer care strategies and ultimately improve patient outcomes in the diagnosis and
prognosis of oral SCC.

8
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11
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Communications, 11(1), 1-11.

12