SAT-358 - Unexpected Duo: Synchronous Colon and Thyroid Cancers with ATM Mutation

Introduction
Germline ATM mutations are recognized moderate-penetrance cancer susceptibility factors, primarily for breast, pancreatic, prostate, and colorectal malignancies. Their role in thyroid cancer is poorly understood, and synchronous primary colorectal and thyroid cancers in the setting of ATM variants are exceedingly rare.
Case Presentation
A 34-year-old woman with no significant past medical or family history presented with progressive right upper quadrant pain, fatigue, and 18-pound unintentional weight loss over five months. Exam revealed right upper quadrant tenderness. Labs showed anemia (Hb 11.5 g/dL) and elevated liver enzymes (ALP 475 U/L, AST 94 U/L, ALT 74 U/L). Imaging revealed multiple liver masses concerning for metastases. Tumor markers were elevated (CEA 94 ng/mL, CA 19-9 6000 U/mL, CA 125 55 U/mL). Liver biopsy confirmed mucinous adenocarcinoma, and colonoscopy revealed invasive sigmoid adenocarcinoma, consistent with metastatic colorectal cancer. Molecular profiling demonstrated KRAS, FGFR2, and ATM mutations with microsatellite-stable disease. Germline testing identified a heterozygous pathogenic ATM variant and variants of uncertain significance in CHEK2 and POT1. During staging, a 2.4 cm right thyroid nodule was incidentally detected; fine-needle aspiration confirmed papillary thyroid carcinoma. She was started on FOLFOX plus bevacizumab; after six cycles, imaging showed disease progression, prompting transition to second-line FOLFIRI plus bevacizumab. Given advanced metastatic disease, thyroidectomy was deferred, and she remains under active multidisciplinary follow-up.
Discussion
This case highlights the complexity of managing incidentally detected papillary thyroid carcinoma in patients with advanced non-thyroid malignancies. ATM plays a critical role in DNA repair and genomic stability, and germline pathogenic variants are increasingly linked to colorectal cancer susceptibility and aggressive behavior. While ATM may explain the early-onset, aggressive metastatic colorectal cancer, its role in thyroid carcinogenesis remains unclear. The coexistence of papillary thyroid carcinoma raises questions about DNA repair–related cancer susceptibility, though a direct causal link cannot be established. Variants of uncertain significance in CHEK2 and POT1 further complicate interpretation in patients with multiple primaries.
Conclusion
Synchronous colorectal and papillary thyroid cancers in a patient with a germline ATM mutation are extremely rare. This case underscores the importance of individualized, multidisciplinary decision-making and highlights the potential, though unproven, role of DNA repair gene mutations in multiple primary malignancies.

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