Introduction: Although the contribution of mosaicism to tumorigenesis emerges during embryonic development, it is a very rare phenomenon in tumor patients. Only a few mosaic RAS mutations have been identified, such as NRAS G12D, NRAS G12S, KRAS G12D. They have been proved to affect the progression of cutaneous tumors and hematologic tumors. Here, we provide the first evidence that mosaic KRAS G12S mutation, a new locus, could significantly promote progression of tumor, papillary thyroid carcinoma.
Case presentation: We report a 58-years-old woman, whose right thyroid neoplasms were diagnosed as papillary thyroid carcinoma five years ago. She had a recurrence accompanied by metastases involving the larynx, hypopharynx, esophagus, internal jugular vein, and bilateral lymph node. The tumor showed no response to sorafenib. Biopsy sample of the recurrence tumor was subjected to targeted next generation sequencing (NGS). The results showed BRAF V600E mutation and TERT promoter mutation of chr5: 1,295,228C>T (C228T) in the tumor sample. Meanwhile, we found KRAS G12S mutations in the tumor sample and normal control tissue. Further examination of the blood cells, plasma, urine and saliva of the patient, all showed KRAS G12S mutations, thus, the patient had mosaic KRAS G12S mutation. Given the patient's tumor had mutation of BRAF V600E, she then received combination therapy with dabrafenib, 150 mg twice daily, and trametinib, 2 mg daily. After 5 months of dabrafenib and trametinib treatment, the tumor was significantly reduced. After that, the disease progressed rapidly, and transformed to anaplastic carcinoma. Targeted NGS results of biopsy sample at this time showed that BRAF V600E mutation and TERT promoter mutation of C228T were remained, and the patient died quickly.
Discussion: Somatic mutations of BRAF V600E and KRAS are mutually exclusive, because both are on the same RAS/RAF/MEK/ERK pathway. Rare patients had co-mutations of them. Only one report about a BRAF V600E PTC patient had an acquired KRAS G12V after the treatment of dabrafenib and trametinib and proved the KRAS G12V was one resistant mechanism of this strategy. Here, this was the first evidence that the mosaic KRAS G12S mutation, but not acquired mutation, resulted in a poorer prognosis of BRAF mutant PTC patient with dabrafenib and trametinib treatment: only 5 months of response in this patient, while 12.6 months of median duration of response in BRF113928 clinical trial of this combo strategy.
Conclusion: This was the first report that mosaic KRAS G12S mutation was associated with cancer, and it was also the first report of mosaicism in thyroid tumor. We speculated that mosaic KRAS G12S mutation was one of the factors leading to more malignant tumor and rapid disease progression. These results suggest that it is important to pay attention to mosaic mutations when detecting the somatic mutations of tumor.
Citation Format: Sheng Yang, Xin Zhang, Xiaoyan Zhang, Kan Liu, Tonghui Ma, Chengyun Geng, Yanling Niu, Xiaohui He. Mosaic KRAS G12S mutation associates with poor outcome in papillary thyroid carcinoma: A case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1199.