bims-mesote 2022-12-04 papers

Issue of 2022–12–04
four papers selected by
Laura Mannarino, Humanitas Research

Mol Oncol. 2022 Nov 30.

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition.

Sabine Paternot, Eric Raspé, Clément Meiller, Maxime Tarabichi, Jean-Baptiste Assié, Frederick Libert, Myriam Remmelink, Xavier Bisteau, Patrick Pauwels, Yuna Blum, Nolwenn Le Stang, Séverine Tabone-Eglinger, Françoise Galateau-Sallé, Christophe Blanquart, Jan P Van Meerbeeck, Thierry Berghmans, Didier Jean, Pierre P Roger.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumors from short survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

Keywords: CDK4 Thr172-phosphorylation; Mesothelioma; biomarker; cell cycle; palbociclib; senescence-associated secretory phenotype

DOI: https://doi.org/10.1002/1878-0261.13351

Lung Cancer. 2022 Nov 19. pii: S0169-5002(22)00686-9. [Epub ahead of print]175 27-35

Usefulness of NF2 hemizygous loss detected by fluorescence in situ hybridization in diagnosing pleural mesothelioma in tissue and cytology material: A multi-institutional study.

Prakasit Sa-Ngiamwibool, Makoto Hamasaki, Yoshiaki Kinoshita, Shinji Matsumoto, Ayuko Sato, Tohru Tsujimura, Kunimitsu Kawahara, Takahiko Kasai, Kei Kushitani, Yukio Takeshima, Kenzo Hiroshima, Akinori Iwasaki, Kazuki Nabeshima.

OBJECTIVES: BAP1, CDKN2A, and NF2 are the most frequently altered genes in pleural mesotheliomas (PM). Discriminating PM from benign mesothelial proliferation (BMP) is sometimes challenging; it is well established that BAP1 loss, determined by immunohistochemistry (IHC), and CDKN2A homozygous deletion (HD), determined by fluorescence in situ hybridization (FISH), are useful. However, data regarding the diagnostic utility of NF2 FISH in PM is limited. Thus, we performed a multi-institutional study examining the utility of NF2 alterations determined by FISH for diagnosing PM in combination with BAP1 loss and CDKN2A HD.
MATERIALS AND METHODS: Multi-institutional PM cases, including 106 surgical and 107 cell block samples as well as 37 tissue cases of benign mesothelial proliferation (BMP) and 31 cell block cases with reactive mesothelial cells (RMC), were collected and analyzed using IHC for BAP1 and FISH for CDKN2A and NF2.
RESULTS: In PM, NF2 FISH revealed hemizygous loss (HL) in 54.7% of tissue cases (TC) and 49.5% of cell block cases (CBC), with about 90% of HL being monosomy. CDKN2A HD or BAP1 loss were detected in 75.5%/65.4% TC or 63.6%/60% CBC, respectively. BMP or RMC showed no BAP1 loss, CDKN2A HD, or NF2 HL. For discriminating PM from BMP, a combination of BAP1 loss, CDKN2A HD, and NF2 HL yielded enhanced sensitivity of 98.1% TC/94.4% CBC. BAP1 loss, CDKN2A HD, or NF2 HL were observed in 69%, 70%, or 58% of epithelioid PM, but in 9%, 91%, or 27% of sarcomatoid PM, respectively. Histotype, histological gradings, and CDKN2A deletion status showed significant differences in overall survival, while BAP1 loss and NF2 HL did not.
CONCLUSION: NF2 HL, consisting predominantly of monosomy, can be detected by FISH in both TC and CBC of PM, and is effective for distinguishing PM from BMP, especially when combined with BAP1 loss and CDKN2A HD.

Keywords: BAP1; CDKN2A; Cell block; FISH; NF2; Pleural mesothelioma

DOI: https://doi.org/10.1016/j.lungcan.2022.11.013

Front Oncol. 2022 ;12 950371

Survival analysis and development of a prognostic nomogram for patients with malignant mesothelioma in different anatomic sites.

Shengteng Shao, Lei Sun, Kun Qin, Xiangfeng Jin, Tengfei Yi, Yuhong Liu, Yuanyong Wang.

Background: Malignant mesothelioma (MMe) is a rare and fatal cancer with a poor prognosis. Our study aimed to compare the overall survival (OS) of MMe patients across various sites and develop a prognostic model to provide a foundation for individualized management of MMe patients.
Methods: From the Surveillance, Epidemiology, and End Results (SEER) database, 1,772 individuals with malignant mesothelioma (MMe) were identified. The X-tile software was used to identify the optimal cut-off point for continuous variables. The Kaplan-Meier method was employed to compare the survival of MMe across different sites. The Cox proportional hazards model was applied to identify the independent risk factors of overall survival (OS) and a nomogram was constructed.
Results: In the survival analysis, MMe originating from the reproductive organs and hollow organs showed a relatively better prognosis than those originating from soft tissue, solid organs, and pleura. Age, gender, location, histological type, grade of differentiation, extent of disease, lymph node status, lymph node ratio (LNR), and chemotherapy were all found to be independent risk variables for the prognosis of MMe patients (P<0.05) in a multivariate Cox analysis and were included in the construction of nomogram. In the training and testing sets, the C-index of the nomogram was 0.701 and 0.665, respectively, and the area under the ROC curve (AUROC) of the 1-, 3-, and 5-year overall survival rate was 0.749, 0.797, 0.833 and 0.730, 0.800, 0.832, respectively. The calibration curve shows that the nomogram is well-calibrated.
Conclusions: This is the first research to examine the prognosis of MMe patients based on the location. However, previous studies often focused on malignant pleural mesothelioma or malignant peritoneal mesothelioma with high incidence. Furthermore, a nomograph with good prediction efficiency was established according to the variables that influence patient survival outcomes, which provides us with a reference for clinical decision-making.

Keywords: SEER database; different anatomic sites; malignant mesothelioma; nomogram; survival

DOI: https://doi.org/10.3389/fonc.2022.950371