Prognostic utility of chromosomal instability detected by fluorescence in situ hybridization in fine-needle aspirates from oral squamous cell carcinomas

One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell division (W-CIN), leads to aneuploidy. Although W-CIN is a hallmark of most cancers, mutations in genes involved in chromosome segregation are exceedingly rare. We discuss an oncogene-induced mitotic stress model that provides a mechanistic framework to explain this paradox. We also review the tumor-promoting and tumor-suppressing consequences of W-CIN. Importantly, we do this in the context of cancer as a complex systemic disease, rather than as a simple linearly progressing disorder that arises from a single abnormal cell population. Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous entities, such as the immune system and the tumor microenvironment. Distinct tissue-specific susceptibilities to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed.

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“…Increased aneuploidy rates reduce disease-free and overall survival and increase the risk of lymph node metastasis. 115,154…”

Section: Squamous Cell Carcinomamentioning

confidence: 99%

The cancer biology of whole-chromosome instability

2013

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“…Genetic and epigenetic changes that drive CIN are particularly attractive targets for synthetic genetic approaches—CIN is frequently observed in tumors and its presence correlates with poor patient outcome [28,29,30,31,32,33,34,35,36]. Conceptually, CIN promotes tumor heterogeneity by decreasing or increasing chromosome numbers or structural rearrangements, which impacts tumor suppressor gene and oncogene copy numbers.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Genetic Targeting of Genome Instability in Cancer

Sajesh

Guppy

McManus

2013

Cancers

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Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets.

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“…For example, CIN is associated with cellular transformation [9,50], tumor evolution and progression including intertumoral and intratumoral heterogeneity [51][52][53], metastasis [54][55][56], and the acquisition of drug resistance [57,58]. Thus, it is perhaps unsurprising that the presence of CIN is typically associated with worse patient outcomes [59][60][61][62]. However, it is interesting to note that there are a small subset of cancers in which the presence of CIN corresponds with improved survival [63][64][65].…”

Section: The Impact Of Cin On Cancer Development and Progressionmentioning

confidence: 99%

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

Vishwakarma

McManus

2020

Cancers

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Chromosome instability (CIN) refers to an ongoing rate of chromosomal changes and is a driver of genetic, cell-to-cell heterogeneity. It is an aberrant phenotype that is intimately associated with cancer development and progression. The presence, extent, and level of CIN has tremendous implications for the clinical management and outcomes of those living with cancer. Despite its relevance in cancer, there is still extensive misuse of the term CIN, and this has adversely impacted our ability to identify and characterize the molecular determinants of CIN. Though several decades of genetic research have provided insight into CIN, the molecular determinants remain largely unknown, which severely limits its clinical potential. In this review, we provide a definition of CIN, describe the two main types, and discuss how it differs from aneuploidy. We subsequently detail its impact on cancer development and progression, and describe how it influences metastatic potential with reference to cancer prognosis and outcomes. Finally, we end with a discussion of how CIN induces genetic heterogeneity to influence the use and efficacy of several precision medicine strategies, including patient and risk stratification, as well as its impact on the acquisition of drug resistance and disease recurrence.

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Prognostic utility of chromosomal instability detected by fluorescence in situ hybridization in fine-needle aspirates from oral squamous cell carcinomas

Cited by 26 publications

References 38 publications

The cancer biology of whole-chromosome instability

The cancer biology of whole-chromosome instability

Synthetic Genetic Targeting of Genome Instability in Cancer

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

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