Genotypic and Biochemical Investigations in Bangladeshi Patients with Papillary Thyroid Carcinoma

Abstract

Background Papillary thyroid cancer (PTC) is the most frequent type of thyroid carcinoma, and exhibits significant molecular and biochemical heterogeneity both within and between populations. It is indolent in nature, but both its diagnosis and prognosis are difficult to predict given its multiple oncogenic pathways and hormonal derangements. This study explores novel somatic variants and their biochemical correlates in a Bangladeshi PTC cohort, aiming to improve risk assessment and promote personalized cancer treatment in underrepresented populations. Methods A cross-sectional comparative study was conducted involving 110 patients with PTC, 100 individuals with benign thyroid conditions, and 100 healthy controls. Targeted next-generation sequencing (NGS) and Sanger validation were employed to identify hotspot and novel intronic variants in NRAS, RB1, HRAS, and RET genes. Concurrently, biochemical profiling included serum thyroid-stimulating hormone (TSH), parathyroid hormone (PTH), calcium, vitamin D, and thyroglobulin (Tg), with correlations analyzed against genotypic status and clinical features. Results Three novel variants -NRAS g.7775T>A, NRAS g.7797G>A, and RB1 c.2039T>A (p.Ile680Asn)—were identified, showing significant enrichment among mutation-positive PTC patients (p < 0.0001), particularly in non-smoking, non-familial cases, suggesting a sporadic mutational origin. The NRAS g.7797G>A variant was associated with early-stage tumors (T1). In contrast, the RB1 c.2039T>A variant was observed in both early and advanced stages, supporting their involvement in early tumorigenesis. Biochemically, PTC patients exhibited markedly elevated TSH levels and reduced serum calcium (p = 0.0305) compared to benign and healthy controls. Individuals carrying the mutation demonstrated more pronounced hypocalcemia and a significant positive correlation between calcium and vitamin D (r = 0.3955, p = 0.0455), a pattern not observed in wild-type carriers. No xxv significant associations were found for Tg or PTH, possibly reflecting heterogeneous expression or unmeasured confounders, such as anti-Tg antibodies. These findings suggest genotype-specific disruptions in calcium–vitamin D–TSH homeostasis and highlight a potential endocrine–genetic crosstalk in PTC pathophysiology. Conclusion The current study provides the first integrative molecular–biochemical profile of Bangladeshi PTC patients, identifying novel NRAS and RB1 variants with potential as early detection and intermediate-risk biomarkers. The observed endocrine dysregulation in mutation carriers underscores the interplay between genetic alterations and systemic metabolism. These findings highlight the clinical utility of combining genotypic screening with metabolic markers for cost-effective, precision-guided management of PTC, especially in resource-limited settings. Future studies should focus on functional validation of these variants and the development of region-specific diagnostic and prognostic frameworks.