Genetic Risk for Aggressive Thyroid Cancer in an Understudied Male Predominant Veteran Population

Va Eastern Colorado Health Care System, Aurora CO

Investigators

Abstract

Thyroid cancer incidence is rising with over 44,000 new cases in 2021 in the United States alone, making it the most common endocrine malignancy. There is a critical gap in knowledge around environmental and genetic risk modifiers for aggressive high-risk thyroid cancer that is a barrier to accurate risk estimation, personalized diagnosis, prognosis, and clinical care. In the Veteran and military populations, there are increased diagnoses of thyroid cancer and an association with Agent Orange exposure. Interestingly, in general, males have a two to three-fold increased mortality associated with thyroid cancer compared to females, despite thyroid cancer being almost three times more common in females. In fact, male sex is associated with a worse overall and recurrence- free survival. In addition, there is a strong hereditary component to this complex disease. Cancer registries estimate genetic effects with highest relative risk of thyroid cancer seen in male relatives of male probands and lower relative risk in female relatives of female probands. Taken together, all of these data suggest there is a sex dimorphism in thyroid cancer with males having more aggressive disease; however, the underlying mechanisms are unknown. We propose to use the Million Veteran Program (MVP) cohort of over 950,000 enrolled Veteran volunteers to investigate the genetic etiology of aggressive thyroid cancer. Because the MVP is male predominant and males have more aggressive thyroid cancer, we propose to perform sex-stratified genome-wide association studies (GWAS) to identify genetic variants for high-risk of recurrence or metastatic thyroid cancer. We also propose to develop a sex-specific polygenic risk score (PRS) to identify patients pre- operatively who are at the highest risk to improve morbidity and mortality. In Aim 1, we will determine the inherited genetic etiology for high-risk differentiated thyroid cancer in the male predominant Veteran population. We will perform a series of sex-stratified GWAS using the MVP clinical and genomic data to identify variants associated with developing high-risk thyroid cancer (and not benign thyroid nodules) seen more often in males. In Aim 2, we will determine the utility of a sex-specific PRS for predicting high-risk differentiated thyroid cancer. We hypothesize that sex-specific PRS will identify patients at the time of presurgical diagnosis who are likely to have high-risk disease and will benefit from more aggressive surgical and adjuvant therapy to reduce morbidity and mortality. The impact of the results of the proposed studies will be transformative to the clinical care for Veterans, and others, with thyroid cancer, especially those with the more aggressive form predominantly seen in males. The results may also provide insight into other endocrine neoplasms and cancers with sex dimorphisms.