Two studies shed new genetic insights into thyroid cancer in Indian patients
The indentification of two critical markers — DUOX2 and THRA — will help in better predicting which patients might face aggressive thyroid cancer disease or recurrence. For papillary thyroid cancer, this might mean developing targeted therapies for the novel subtype (iBR) or using DUOX2 for early detection. For anaplastic thyroid cancer, targeting THRA-driven plasticity could lead to breakthroughs for a cancer with few options
Two of our studies, led by our joint graduate student Vaishakhi Trivedi, published recently unveil transformative insights into the genetic underpinnings of thyroid cancer in Indian patients; the studies focus on papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). These findings, which may turn out to be game-changers, reveal how specific genetic changes drive these cancers, opening the door for innovative pathways for personalised diagnostics and treatments. These studies are from a joint collaboration between the Department of Genetics, University of Delhi South Campus , New Delhi, and Department of Medical Oncology, Tata Memorial Hospital, Mumbai, and are published in the journal JCO Global Oncology on May 29, 2025 and July 17, 2025.
Uncovering genetic risks
Papillary thyroid cancer, the most common thyroid malignancy, is often treatable but varies widely in its behaviour. In our first study, we analyzed 100 papillary thyroid cancer samples from Indian patients using whole-exome sequencing, a technique that examines the DNA of both tumor and healthy cells. We uncovered critical genetic mutations that explain why some patients face worse outcomes.
A major discovery was the presence of germline mutations in a particular gene —DUOX2 — in approximately 8.8% of patients. This gene is critical for thyroid hormone production, and its mutations are associated with congenital hypothyroidism, a condition impairing hormone synthesis and potentially leading to developmental challenges. Our work is the first to propose that mutations in this gene may also predispose individuals to papillary thyroid cancer, with affected patients showing higher cancer recurrence rates and worse prognosis. This finding has the potential to reshape clinical practice by enabling early screening for at-risk individuals, allowing for earlier detection and intervention to prevent disease progression.
Distinct molecular subtypes
We identified two distinct molecular subtypes of papillary thyroid cancer in the Indian population. The first is the BRAF-RAS-driven subtype that is already known in certain populations outside India. In this subtype, approximately 62% of Indian patients harboured mutations in four genes — BRAF (35.4%), KRAS (3.8%), HRAS (5.1%), or NRAS (17.7%). These mutations drive cancer growth, with BRAF mutations often linked to aggressive tumours that metastasise beyond the thyroid. The high prevalence of BRAF and RAS mutations in Indian patients underscores the need for targeted therapies, which have shown promise in other populations and could therefore be adapted for Indian patients.
The second subtype we discovered is a novel subtype — independent of BRAF-RAS (iBR) — which lacks the hallmark BRAF or RAS mutations. Instead, this subtype is characterised by unique mutations in two genes — SMAD4 and TG. Patients with this novel subtype exhibited higher recurrence rates and poorer recurrence-free survival, indicating potential resistance to standard treatments such as radioiodine therapy. This subtype reveals a new layer of complexity in papillary thyroid cancer, highlighting how genetic diversity contributes to distinct disease behaviours and necessitates alternative therapeutic approaches.
These discoveries underscore the unique genetic landscape of papillary thyroid cancer in Indian patients compared with others, such as Caucasians, where BRAF mutations are more frequent at 58% vis-à-vis 35.4% in Indians. Our work suggests that screening for DUOX2 mutations could become routine, while the novel subtype’s aggressive nature calls for new treatment strategies targeting its unique genetic profile.
Decoding cellular plasticity in anaplastic thyroid cancer
Anaplastic thyroid cancer, though rare (1-2% of thyroid cancers), is highly aggressive and often lethal. In our second study, we analysed 68 anaplastic thyroid cancer samples from Indian patients, providing the first comprehensive genetic profile of this cancer in the Indian population. Our findings spotlight a novel genetic driver that could unlock new treatment avenues.
At 42%, we observed frequent mutations in the TP53 gene, a well-known driver of aggressive cancers, alongside other genes — BRAF (10.3%) and RAS genes (55% combined, including KRAS, NRAS, and HRAS). Most notably, we identified mutations in one particular gene — THRA — in 11% of patients, a significant contrast to their rarity in Caucasian anaplastic thyroid cancer patients. This gene regulates thyroid hormone (T3 and T4) signaling, which shapes cell development and identity. Our findings indicate that mutations in this gene may disrupt the hormone signaling process, promoting cellular plasticity — a hallmark of cancer where cells lose their specialised identity, becoming more aggressive and adaptable. This discovery provides a new perspective on the biology of anaplastic thyroid cancer, revealing how cellular plasticity contributes to its aggressive behaviour.
Patients with mutations in the THRA gene, particularly when combined with TP53 or other hallmark mutations, had worse outcomes, suggesting a synergistic effect that fuels anaplastic thyroid cancer’s lethality. Unlike papillary thyroid cancer, where THRA mutations were absent in purely papillary cases, their presence in anaplastic thyroid cancer points to a role in its undifferentiated state. Identifying THRA mutations in anaplastic thyroid cancer patients could guide us toward therapies that target cellular plasticity, offering hope for a disease with limited options.
Why our findings matter
Our studies demonstrate that thyroid cancer in Indian patients display distinct genetic signatures, challenging the applicability of universal treatment approaches. For instance, in the case of papillary thyroid cancer, the identification of DUOX2 mutations establishes a novel link between congenital hypothyroidism and cancer risk, positioning DUOX2 as a potential screening biomarker. The discovery of the novel subtype (iBR) highlights a patient group requiring alternative therapies targeting non-BRAF/RAS pathways, advancing the move toward precision medicine tailored to individual cancer profiles.
In the case of anaplastic thyroid cancer, the identification of THRA mutations opens a new frontier in understanding cellular plasticity. Therapies aimed at restoring THRA function could potentially re-differentiate cancer cells, reducing their aggressiveness. The synergy between THRA and TP53 mutations suggests that combination therapies targeting these pathways could be particularly effective, offering a promising direction for improving outcomes in this deadly disease.
Vision for the future
Our findings mark a significant step toward personalised thyroid cancer care. By identifying two critical markers — DUOX2 and THRA — we are in a position to better predict which patients might face aggressive disease or recurrence. For papillary thyroid cancer, this might mean developing targeted therapies for the novel subtype (iBR) or using DUOX2 for early detection. For anaplastic thyroid cancer, targeting THRA-driven plasticity could lead to breakthroughs for a cancer with few options.
Larger studies are indeed necessary to validate our findings and translate them into clinical practice. Innovations like CRISPR-based gene editing or small-molecule drugs targeting specific mutations could be explored. Integrating genetic profiling into routine diagnostics could tailor treatments to each patient’s unique cancer profile, improving outcomes and quality of life.
In conclusion, our work illuminates the complex genetic landscape of thyroid cancer in Indian patients, revealing new risk factors and molecular subtypes. By harnessing these insights, we aim to develop smarter, more effective strategies to combat papillary thyroid cancer and anaplastic thyroid cancer, offering hope for better survival and recovery.
