Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis.

Objective: The aim of this study was to compare the molecular profiling, including somatic mutation and somatic copy number variation (SCNV), between human epidermal growth factor receptor 2 (HER2)-positive (HER2+) and HER2-negative (HER2-) gastric cancer patients.

Patients and methods: Tumor samples were collected from 15 gastric cancer patients, including 10 HER2+ samples and five HER2- samples, which were diagnosed by immunohistochemistry. Whole-genome sequencing was performed by Illumina HiSeq PE150 instrument, along with somatic single nucleotide variant (SNV), somatic structural variation (SV) and SCNV analyses.

Results: The average number of somatic SNVs and mutation spectrum were similar between HER2+ and HER2- samples. Transition of C>T was the main type of mutation. For somatic SV, number of intrachromosomal translocation (2,850.3±1,260.4 vs 1,157±586.6, P =0.015) and insertion of large fragment (1,125.6±457.4 vs 500±138.9, P =0.002) in HER2+ samples were higher than those in HER2- samples. For all samples, lysine methyltransferase 2C ( KMT2C ), ZNF91 , TAF1 and MAP4 genes were identified as new significant mutated driver genes. KMT2C gene mutations were mainly detected in HER2+ samples (7/10), which were correlated with the lysine degradation pathway. SERF2 gene mutations were more common in HER2- samples (3/5) than in HER2+ samples (1/10). Copy number gain was the major type of SCNV in both groups, and the average number of SCNVs was similar. In the HER2+ samples, by using the GISTIC algorithm, amplification of known driver genes cyclin-dependent kinase 12 ( CDK12, 6/10) and RARA (5/10) was mainly observed, and other amplifications including JUP , GJD3 , KRT39 , CDC6 , RAPGEFL1 , WIPF2 , FAM65C , KLF5 , DACH1 and PIBF1 genes were also observed. Amplifications of solute carrier family 12 member 7 ( SLC12A7, 5/5), TTC40 (4/5) and GALNT9 (4/5) genes were mainly detected in HER2- samples.

Conclusion: Differences in genomic landscape between HER2+ and HER2- gastric cancer samples were revealed in this study. KMT2C mutation and CDK12 amplification were mainly detected in HER2+ gastric cancer, whereas SERF2 mutation and SLC12A7 amplification were detected in HER2- gastric cancer.