Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature

Abstract

Background The microphthalmia-associated transcription factor gene (MITF) belongs to the MYC supergene family and plays an important role in melanocytes’ homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma. Case presentation We describe a cohort of ten individuals who harbor the same MITF c.952G > A (p.Glu 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer; 1 cervical cancer; 1 colon cancer; 1 melanoma; 1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives. Conclusions Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.

Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

“… 42 Moreover, a study from a Brazilian cohort from a hereditary cancer registry described a prevalence of 0.9% for this variant (10/1056 patients), with breast cancer being the most common cancer in probands and their relatives and no description of sarcomas. 43 …”

“…42 Moreover, a study from a Brazilian cohort from a hereditary cancer registry described a prevalence of 0.9% for this variant (10/1056 patients), with breast cancer being the most common cancer in probands and their relatives and no description of sarcomas. 43 Recent studies have suggested that sarcoma susceptibility can result not only from monogenic high-risk variants but also from a combined effect of multiple less penetrant variants contributing to sarcoma risks through a polygenic risk model. 5 Specifically, polygenic effects and monoallelic germline variants in DNA damage response (DDR) genes were suggested to predispose patients to young-onset translocation-associated sarcoma subtypes, 5 as was later shown to be the case for FANCC variants in Ewing sarcomas.…”