Mode of Cell Cycle Dysregulation in Cancer Formation Affects Disease Characteristics

Various modes of cell cycle checkpoint kinase dysregulation can determine subtype, metastatic potential, and treatment responsiveness of different forms of breast cancer, a study published in Science Advances found.

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The importance of cell cycle checkpoint kinase dysregulation in the evolution of breast cancer has been well-documented, yet until now there has been lacking research on whether differences in the dysregulation process can indicate breast cancer incidence or seriousness.

The study authors aimed to tackle this issue by systematically evaluating and determining the relative contribution of dysregulation of each cell cycle to the formation of specific types of tumors.

Firstly, the investigators determined the frequency of both germline and somatic mutations in each of the 4 cell cycle checkpoint kinase genes in triple negative breast cancer (TNBC) and estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes: ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2), ataxia-telangiectasia and Rad3-related protein (ATR), and CHEK1.

Researchers determined that, on an individual gene level, CHEK2 had a greater than 5-fold enrichment for mutations (29 of 3382 versus 0 of 640, P = 0.001) in ER-positive/HER2-negative samples relative to TNBC samples. Furthermore, there was no statistically significant enrichment for ATM, ATR, and CHEK1 in either breast cancer subtype.

The investigators tested whether germline mutations in CHEK2 can alter progesterone receptor (PR) positivity, and they found that neither germline nor somatic mutations affect positivity. Investigators further determined that, conversely, somatic mutations in ATM are associated with a 2-fold enrichment for PR negativity.

A notable discovery was that women who are carriers of germline variants in CHEK2 are predisposed to the incidence of premenopausal ER-positive/HER2-negative breast cancer. Researchers discovered this by analyzing an experimental demonstration in genetically engineered mice.

Additionally, researchers found that either a somatic or germline mutation of CHEK2 resulted in a higher likelihood of a patient being diagnosed with metastatic rather than primary ER-positive/HER2-negative breast cancer, a discovery that is supported by previous studies on the topic.

Continuing analysis of CHEK2 found that patients with the mutation appear resistant to endocrine monotherapy despite their cancer being highly PR-positive. On the other hand, researchers determined that ATM mutations enrich for incidence of primary ER-positive/HER2-negative breast cancer that is preferentially PR-negative, which is typically associated with more aggressive disease, though researchers did not find associations between ATM mutations and poor patient outcomes.

In what the study authors called a previously unidentified discovery, they uncovered a role for co-mutation of ATR and TP53, and that the association of this co-mutation with metastasis-free survival is seemingly significantly stronger than that of mutation of either gene alone.

In summing up their collective research, the study investigators suggested that knowledge of the mode of cell cycle dysregulation during tumorigenesis can be effectively leveraged to improve characterization of cancer subtypes. However, they noted that other kinases were not considered in their analysis but warrant further investigating.

The investigators wrote that the results of their study demonstrate the clear differences in the impact of dysregulation on the essential characteristics of tumors and shed new light into how decisions regarding cell cycle regulation can direct the course of ensuing disease.

“Further evidence that early loss of specific cell cycle checkpoint kinases essentially serves as a decision point for evolution of cancers with specific prognostic and progressive tendencies may argue for an improved system of cancer classification based on the mode of cell cycle checkpoint inactivation to guide selection of therapeutics,” the study authors concluded.

Reference

Oropeza E, Seker S, Carrel S, et al. Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness. Sci Adv. 2023; 9(26)eadf2860. doi:10.1126/sciadv.adf2860