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Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness.

ABSTRACT: Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that ATM mutation predisposes the diagnosis of primary estrogen receptor (ER)⁺/human epidermal growth factor (HER)2^- cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, premenopausal ER⁺/HER2^- breast cancer (P = 0.001) that is treatment-resistant (HR = 6.15, P = 0.01). Lastly, while mutations in ATR alone are rare, ATR/TP53 co-mutation is 12-fold enriched over expected in ER⁺/HER2^- disease (P = 0.002) and associates with metastatic progression (HR = 2.01, P = 0.006). Concordantly, ATR dysregulation induces metastatic phenotypes in TP53 mutant, not wild-type, cells. Overall, we identify mode of cell cycle dysregulation as a distinct event that determines subtype, metastatic potential, and treatment responsiveness, providing rationale for reconsidering diagnostic classification through the lens of the mode of cell cycle dysregulation..

SUBMITTER: Oropeza E

PROVIDER: S-EPMC10313178 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness.

Oropeza Elena E Seker Sinem S Carrel Sabrina S Mazumder Aloran A Lozano Daniel D Jimenez Athena A VandenHeuvel Sabrina N SN Noltensmeyer Dillon A DA Punturi Nindo B NB Lei Jonathan T JT Lim Bora B Waltz Susan E SE Raghavan Shreya A SA Bainbridge Matthew N MN Haricharan Svasti S

Science advances 20230630 26

Cell cycle dysregulation is prerequisite for cancer formation. However, it is unknown whether the mode of dysregulation affects disease characteristics. Here, we conduct comprehensive analyses of cell cycle checkpoint dysregulation using patient data and experimental investigations. We find that ATM mutation predisposes the diagnosis of primary estrogen receptor (ER)+/human epidermal growth factor (HER)2- cancer in older women. Conversely, CHK2 dysregulation induces ...[more]

PMID: 37390209

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Project description:BackgroundClustering analysis of microarray data is often criticized for giving ambiguous results because of sensitivity to data perturbation or clustering techniques used. In this paper, we describe a new method based on principal component analysis and ensemble consensus clustering that avoids these problems.ResultsWe illustrate the method on a public microarray dataset from 36 breast cancer patients of whom 31 were diagnosed with at least two of three pathological stages of disease (atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Our method identifies an optimum set of genes and divides the samples into stable clusters which correlate with clinical classification into Luminal, Basal-like and Her2+ subtypes. Our analysis reveals a hierarchical portrait of breast cancer progression and identifies genes and pathways for each stage, grade and subtype. An intriguing observation is that the disease phenotype is distinguishable in ADH and progresses along distinct pathways for each subtype. The genetic signature for disease heterogeneity across subtypes is greater than the heterogeneity of progression from DCIS to IDC within a subtype, suggesting that the disease subtypes have distinct progression pathways. Our method identifies six disease subtype and one normal clusters. The first split separates the normal samples from the cancer samples. Next, the cancer cluster splits into low grade (pathological grades 1 and 2) and high grade (pathological grades 2 and 3) while the normal cluster is unchanged. Further, the low grade cluster splits into two subclusters and the high grade cluster into four. The final six disease clusters are mapped into one Luminal A, three Luminal B, one Basal-like and one Her2+.ConclusionWe confirm that the cancer phenotype can be identified in early stage because the genes altered in this stage progressively alter further as the disease progresses through DCIS into IDC. We identify six subtypes of disease which have distinct genetic signatures and remain separated in the clustering hierarchy. Our findings suggest that the heterogeneity of disease across subtypes is higher than the heterogeneity of the disease progression within a subtype, indicating that the subtypes are in fact distinct diseases.

Dataset Information

Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness.

Publications

Molecular portraits of cell cycle checkpoint kinases in cancer evolution, progression, and treatment responsiveness.

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