Novel germline variants of MUC3A in a patient with ER+ breast cancer and signet-ring cell stomach adenocarcinoma

Abstract

BackgroundPrimary gastric cancer after breast cancer surgery and chemotherapy is rare and their genetic factors are poorly understood. In this case study, the exonic sequences of a gastric cancer (GC) patient with a previous history of breast cancer were explored. Materials and methodsThe study involves a 58-year-old diabetic patient from Mizoram, Northeast India underwent surgery and chemotherapy for estrogen receptor-positive breast cancer. The patient contracted tuberculosis and was later diagnosed with metastatic GC after 5 years and underwent subtotal gastrectomy followed by chemotherapy. Genomic DNA was isolated from the patient blood, whole exome sequencing was performed, and analyzed for germline variants. The variants were compared with exome data from additional 21 GC patients and 27 healthy controls. Statistical analysis was performed to compare the occurrence of variants between cancer and healthy control datasets. ResultsThe patient had CDH1, BRCA1, and BRCA2 mutations, while a rare variant rs750547893 in SMARCA4 was observed. Furthermore, an unusual phenomenon was observed in the MUC3A with 80 missense variants, including 19 novel variants. One-way ANOVA revealed a significant difference in the mean number of missense MUC3A variants observed between GC and healthy controls (F = 317.92, P = 1.50e-22). Fisher's exact test on the number of MUC3A missense variants in GC and healthy controls revealed 70 variants that were significantly associated with cancer (P < 0.05) and out of which 20 variants were present exclusively in the case, including 9 novel variants. ConclusionsThe rare variant, rs750547893 in SMARCA4 was not reported in the database of over 1000 healthy Indians (IndiGenomes database). Due to conflicting clinical interpretation, the variant is classified as the variant of uncertain significance (VUS), although it is reported for hereditary cancer predisposing syndrome in ClinVar. Furthermore, Statistical analysis revealed that these MUC3A variants could be a significant factor in cancer. The presence of such missense variants in MUC3A could affect the mucus integrity and might contribute to multiple types of cancer development in the patient. Due to the unavailability of pathogenicity information from the clinical point of view, the variants are classified as VUS. This is the first report of such a large number of variants in the MUC3A gene and future efforts may reveal the clinical significance.