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Simple Summary: Galectins are a family of β-galactoside binding proteins whose levels are altered in various stages of different types of cancer. This study provides an analytical comparison of 50 frequently mutated genes in two common cancers and the serum levels of the galectin proteins. The goal is the revelation of potential relationships between the mutation status of these genes and serum levels of galectins. We found that mutations in the KIT gene (which codes for the proto-oncogene c-KIT protein) are associated with increased circulating levels of certain galectins. We also found that patient samples originating from brain tissue have a higher likelihood of having a mutation in the KIT gene. Understanding the relationship between cancer-critical gene mutations and serum galectin levels could provide a feasible and non-invasive avenue to better understand the tumor's unique genetic profile. To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the mutation status of 50 known cancer-critical genes, which were determined using multiplex PCR in tumors of the same patients. Mutations in the KIT proto-oncogene, which codes for the c-Kit protein, a receptor tyrosine kinase, correlated with higher levels of galectins -1, -3, -8, and -9 in breast cancer patients and galectin-1 in non-small cell lung cancer patients. Mutations in the KIT gene were more likely found in brain metastases from both of these primary cancers. The most common KIT mutation in our panel was p.M541L, a missense mutation in the transmembrane domain of the c-Kit protein. These results demonstrate an association between KIT oncogenic signaling and elevated serum galectins in patients with metastatic disease. Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments. [ABSTRACT FROM AUTHOR]