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Simple Summary: This study focused on the identification of rare variants that are associated with high-risk colorectal cancer (CRC) from the Middle Eastern region. This study analyzed DNA samples from 146 patients with CRC and from 1395 healthy individuals. We identified rare inactivating variants in the APC gene that are strongly linked to CRC, increasing the risk approximately 60-fold. Other significant genes harboring rare damaging variants were also identified. These results may have implications for genetic counseling and the early detection of CRC in the Middle Eastern population. Background: Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enriched in high-impact rare alleles, which might play a crucial role in the etiology and susceptibility of CRC. Methods: In this study, an exome-wide association analysis was performed in 146 patients with high-risk CRC in the Middle East and 1395 healthy controls. The aim was to identify rare germline variants in coding regions and their splicing sites associated with high-risk CRC in the Middle Eastern population. Results: Rare inactivating variants (RIVs) in APC had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, p = 5.13 × 10−12), whereas RIVs in RIMS1, an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, p = 2.03 × 10−8). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold (p < 2.5 × 10−6). Based on the sequence kernel association test, nonsynonymous variants in six genes (TNXB, TAP2, GPSM3, ADGRG4, TMEM229A, and ANKRD33B) had a significant association with high-risk CRC. RIVs in APC—the most common high-penetrance genetic factor—were associated with patients with high-risk CRC in the Middle East. Individuals who inherited APC RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. Conclusions: We identified new potential CRC predisposition variants in other genes that could play a role in CRC inheritance. However, large collaborative studies are needed to confirm the association of these variants with high-risk CRC. These results provide information for counseling patients with high-risk CRC and their families in our population. [ABSTRACT FROM AUTHOR]

Polo-like kinase 1 (PLK1) is a serine/threonine–protein kinase essential for regulating multiple stages of cell cycle progression in mammals. Aberrant regulation of PLK1 has been observed in numerous human cancers and is linked to poor prognoses. However, its role in the pathogenesis of colorectal cancer (CRC) in the Middle East remains unexplored. PLK1 overexpression was noted in 60.3% (693/1149) of CRC cases and was significantly associated with aggressive clinico-pathological parameters and p-ERK1/2 overexpression. Intriguingly, multivariate logistic regression analysis identified PLK1 as an independent predictor of lymph node metastasis. Our in vitro experiments demonstrated that CRC cells with high PLK1 levels were resistant to 5-Fu treatment, while those with low PLK1 expression were sensitive. To investigate PLK1′s role in chemoresistance, we used the specific inhibitor volasertib, which effectively reversed 5-Fu resistance. Interestingly, forced PLK1 expression activated the CRAF-MEK-ERK signaling cascade, while its inhibition suppressed this cascade. PLK1 knockdown reduced epithelial-to-mesenchymal transition (EMT) progression and stem cell-like traits in 5-Fu-resistant cells, implicating PLK1 in EMT induction and stemness in CRC. Moreover, silencing ERK1/2 significantly mitigated chemoresistance, EMT, and stemness properties in CRC cell lines that express PLK1. Furthermore, the knockdown of Zeb1 attenuated EMT and stemness, suggesting a possible link between EMT activation and the maintenance of stemness in CRC. Our findings underscore the pivotal role of PLK1 in mediating chemoresistance and suggest that PLK1 inhibition may represent a potential therapeutic strategy for the management of aggressive colorectal cancer subtypes. [ABSTRACT FROM AUTHOR]

Objective. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, represents the most prevalent autoimmune thyroid disorder globally. The potential influence of HT on the clinical and pathological attributes, as well as the clinical outcomes of differentiated thyroid carcinoma (DTC), remains a point of ongoing debate within the medical community. The central focus of this study was to analyze the influence of HT on clinico‐pathological characteristics and its prognostic impact in a large cohort of DTC from Middle Eastern ethnicity. Design, Patients, Measurements. An extensive analysis involving 1822 DTC patients was conducted to determine the association with clinico‐pathological characteristics as well as prognosis, using Chi‐square tests and Kaplan‐Meier curves. Results. 23.9% (435/1822) of DTC patients were diagnosed with HT. Univariate analysis revealed a positive correlation between presence of HT and clinico‐pathological factors such as female gender, younger age, and early stage tumor. In contrast, HT demonstrated a negative association with several aggressive clinical features, including extrathyroidal extension, distant metastasis, recurrent/persistent disease and high‐risk categorization by the American Thyroid Association (ATA) guidelines. Despite HT being associated with favorable clinico‐pathological features in Middle Eastern DTC patient, our study found no significant influence on overall survival or recurrence‐free survival. Conclusion. The finding of an association between HT and favorable clinico‐pathological characteristics, but lack of impact on prognosis, underscores the complexity of HT‐DTC relationship, necessitating further comprehensive research to fully understand these interactions. [ABSTRACT FROM AUTHOR]

Heart failure is associated with the reactivation of a fetal cardiac gene programme that has become a hallmark of cardiac hypertrophy and maladaptive ventricular remodelling, yet the mechanisms that regulate this transcriptional reprogramming are not fully understood. Using mice with genetic ablation of calcium/calmodulin-dependent protein kinase II δ (CaMKIIδ), which are resistant to pathological cardiac stress, we show that CaMKIIδ regulates the phosphorylation of histone H3 at serine-10 during pressure overload hypertrophy. H3 S10 phosphorylation is strongly increased in the adult mouse heart in the early phase of cardiac hypertrophy and remains detectable during cardiac decompensation. This response correlates with up-regulation of CaMKIIδ and increased expression of transcriptional drivers of pathological cardiac hypertrophy and of fetal cardiac genes. Similar changes are detected in patients with end-stage heart failure, where CaMKIIδ specifically interacts with phospho-H3. Robust H3 phosphorylation is detected in both adult ventricular myocytes and in non-cardiac cells in the stressed myocardium, and these signals are abolished in CaMKIIδ-deficient mice after pressure overload. Mechanistically, fetal cardiac genes are activated by increased recruitment of CaMKIIδ and enhanced H3 phosphorylation at hypertrophic promoter regions, both in mice and in human failing hearts, and this response is blunted in CaMKIIδ-deficient mice under stress. We also document that the chaperone protein 14-3-3 binds phosphorylated H3 in response to stress, allowing proper elongation of fetal cardiac genes by RNA polymerase II (RNAPII), as well as elongation of transcription factors regulating cardiac hypertrophy. These processes are impaired in CaMKIIδ-KO mice after pathological stress. The findings reveal a novel in vivo function of CaMKIIδ in regulating H3 phosphorylation and suggest a novel epigenetic mechanism by which CaMKIIδ controls cardiac hypertrophy.

Furin belongs to the pro‐protein convertases (PCs) family and its aberrant expression has been documented in various types of cancers; however, its role in thyroid cancer remains unclear. We investigated the expression of furin in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. Furin overexpression was observed in 44.6% of all PTC cases and was significantly associated with aggressive clinicopathological parameters and poor outcomes. We show that the knockdown of FURIN suppresses tumor growth, proliferation, migration, invasion, spheroid growth, and progression of epithelial‐to‐mesenchymal transition (EMT) in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) mutant cells, whereas its overexpression in BRAF wild‐type PTC cell lines reversed the effect. FURIN knockdown in the BRAF mutant cell line led to reduced tumor growth and increased apoptosis. Mechanistically, FURIN knockdown led to MEK/ERK pathway suppression in BRAF mutant cells, although inhibition of MEK did not affect furin expression, which suggests that furin acts through the MEK/ERK pathway. Furthermore, our study revealed the synergistic antitumor effect of furin depletion and anti‐MEK inhibitor treatment. Overall, these results indicate that furin is an important prognostic marker in Middle Eastern PTC and that it plays a crucial role in BRAF‐associated MAP/ERK pathway activation and tumorigenesis. Furin inhibition could be a potential therapeutic target for aggressive PTC. [ABSTRACT FROM AUTHOR]