scholarly journals POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer

2020 ◽  
Vol 9 (9) ◽  
pp. 923-932
Author(s):  
Abdul K Siraj ◽  
Rong Bu ◽  
Maham Arshad ◽  
Kaleem Iqbal ◽  
Sandeep Kumar Parvathareddy ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Middle Eastern ◽  
Stage Iv ◽  
Pathogenic Variant ◽  
Eastern Region ◽  
Papillary Thyroid ◽  
Pathogenic Variants ◽  
Middle Eastern Population ◽  
Low Expression

Thyroid cancer is the most frequent endocrine cancer with an increasing incidence rate worldwide and is the second most common malignancy among females in Saudi Arabia. Papillary thyroid cancer (PTC) is the most common subtype. Germline pathogenic variants in the proofreading domain of the POLE and POLD1 genes predispose to several types of cancers. However, the role of pathogenic variants of these two genes in PTC remains unknown. Capture sequencing, Sanger sequencing and immunohistochemistry were performed on 300 PTC cases from the Middle Eastern region. One germline pathogenic variant each of POLE (1/300, 0.33%) and POLD1 (1/300, 0.33%) genes was identified. Low expression of POLD1 was detected in 46.5% (133/286) of cases and was significantly associated with the follicular variant of PTC (P = 0.0006), distant metastasis (P = 0.0033) and stage IV tumours (P = 0.0081). However, no somatic pathogenic variant was detected in POLE gene. Furthermore, low expression of POLE was noted in 61.7% (175/284) of cases with no significant clinicopathological associations. Our study shows that pathogenic variant in the POLE and POLD1 proofreading domain is a cause of PTC and low expression of POLD1 is associated with poor prognostic markers in the Middle Eastern population. Further studies from different geographic populations are needed to determine the frequency and spectrum of proofreading domain pathogenic variants in POLE and POLD1 genes and in PTC from different ethnicities.

Abstract 730: Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up

2021 ◽  
Author(s):  
Abdul K. Siraj ◽  
Sandeep K. Parvathareddy ◽  
Zeeshan Qadri ◽  
Saud Azam ◽  
Felisa De Vera ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hazard Rate ◽  
Middle Eastern ◽  
Papillary Thyroid ◽  
Long Term Follow Up

scholarly journals Annual Hazard Rate of Recurrence in Middle Eastern Papillary Thyroid Cancer over a Long-Term Follow-Up

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3624
Author(s):  
Abdul K. Siraj ◽  
Sandeep Kumar Parvathareddy ◽  
Zeeshan Qadri ◽  
Khawar Siddiqui ◽  
Saif S. Al-Sobhi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hazard Rate ◽  
Tumor Recurrence ◽  
Cox Regression ◽  
Middle Eastern ◽  
Treatment Strategies ◽  
Recurrence Risk ◽  
Papillary Thyroid ◽  
Cox Regression Analysis

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were further analyzed according to clinical variables predictive of early (≤5 years) and late (>5 years) recurrence using Cox regression analysis to identify patient populations that remain at risk. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 and 2 years (3.7%), with a second smaller peak between 13 and 14 years (3.2%). Patients receiving radioactive iodine (RAI) therapy had lower recurrence hazard compared to those who did not (1.5% vs. 2.7%, p = 0.0001). Importantly, this difference was significant even in intermediate-risk PTC patients (0.7% vs. 2.3%; p = 0.0001). Interestingly, patients aged ≥55 years and having lymph node metastasis were at persistent risk for late recurrence. In conclusion, we confirmed the validity of the double-peaked time-varying pattern for recurrence risk in Middle Eastern PTC patients and our findings could help in formulating individualized treatment and surveillance plans.

scholarly journals Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Abdul K. Siraj ◽  
Sandeep Kumar Parvathareddy ◽  
Rong Bu ◽  
Kaleem Iqbal ◽  
Sarah Siraj ◽  
...  
Keyword(s):  
Endometrial Carcinoma ◽  
Middle Eastern ◽  
Germline Mutations ◽  
Cowden Syndrome ◽  
Eastern Region ◽  
Variant Interpretation ◽  
Multiple Cancer ◽  
Middle Eastern Population ◽  
Capture Sequencing ◽  
Low Expression

Abstract Background Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2–5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of POLE and POLD1 genes in a large cohort of ECs from Middle Eastern region. Methods We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of POLE and POLD1 genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster. Results In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in POLE and POLD1 proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring POLE mutation showed high nuclear expression of POLE protein, whereas, of the two POLD1 mutant cases, one case showed high expression and another case showed low expression of POLD1 protein. Conclusions Our study shows that germline mutations in POLE and POLD1 proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including POLE and POLD1.

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