Oncogenic ERBB3 mutations altering p.Val104 is rare in acute leukemias and non‐Hodgkin lymphomas

To the Editor: Receptor tyrosine kinases (RTK) that regulate biological processes in cell growth and survival are a major oncogene family. The ERBB family of RTK consists of ERBB1 (EGFR/HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4) (1). When compared to the other three ERBBs, ERBB3 has a weaker kinase activity (1). Upon binding with ligand, ERBB3 heteromerizes with other RTK, especially ERBB2, and transmits downstream signals (1). Mounting evidence indicates that ERBB genes are altered in human cancers. For example, lung adenocarcinomas harbor EGFR mutations and breast cancers harbor ERBB2 amplification (2, 3). These genetic alterations are therapeutically targeted and currently used in clinic (2, 3), indicating that oncogenic mutations of ERBB genes are common targets of genetic alterations in human cancers. A recent study discovered that ERBB3 somatic mutations were common in colorectal and gastric cancers (~11%), and less common in other solid cancers (4). Of note, most of the ERBB3 mutations were discovered in the extracellular ligand-binding domain (ECD) and were recurrent at specific amino acids. Of these, somatic mutations altering an amino acid residue at 104 (p.Val104Met and p.Val104Leu) were the most common recurrent mutations. These mutations conferred transformation activities in cells in a ligand-independent fashion. Furthermore, anti-ERBB antibodies and small molecule inhibitors blocked the mutant ERBB3-related oncogenic activities. Although ERBB3 signaling and alterations are well known in solid tumors, but they are not known well in hematologic neoplasia (5). Thus, it is interesting to know whether recurrent ERBB3 mutation occurs in neoplasia from hematopoietic tissues as well. For this, we analyzed somatic mutations of ERBB3 gene using genomic DNA from in fresh bone marrow aspirates of 811 hematologic tumors (acute myelogenous leukemias (AML), acute lymphoblastic leukemias (ALL), multiple myelomas, and myelodysplastic syndromes) (Table 1) by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) assay. Also, we analyzed the gene in paraffin-embedded tissues of 63 non-Hodgkin lymphomas (NHL). Approval was obtained from the Catholic University of Korea, College of Medicine’s institutional review board for this study. Genomic DNA each from tumor cells and normal cells (remission bone marrow cells in the cases of leukemias) was used in this study. Genomic DNA each from tumor cells and corresponding normal cells was amplified with a primer pair covering the exon 3 of ERBB3 gene that contained coding sequences of amino acid residue Val104. Radioisotope was incorporated into the PCR products for detection by autoradiogram. After the SSCP, DNAs showing mobility shifts were cut out from the dried gel, and re-amplified for 30 cycles using the same primer sets. In colon carcinomas, we were able to find the recurrent mutations p.Val104Met and p.Val104Leu, which were subsequently used as positive controls in SSCP. However, none of the SSCP from the hematologic neoplasia revealed aberrantly migrating bands compared with wild-type bands from the normal tissues (Fig. 1), indicating there was no evidence of ERBB3 mutation altering the Val104 in the neoplasia analyzed. To confirm the SSCP results, we repeated the experiments twice and found that the data were consistent.