A germline MUTYH truncating variant in a luminal a breast cancer patient: expanding the hereditary landscape beyond colorectal cancer

Yuniar Harris Prayitno; Fahreza Saputra; Noorwati Sutandyo

doi:10.22146/inajbcs.v57i3.Supplement.24275

Yuniar Harris Prayitno Haematology and Medical Oncology Department, Dharmais National Cancer Centre Hospital, Jakarta, Indonesia
Fahreza Saputra Clinical Research Unit, Dharmais National Cancer Centre Hospital, Jakarta, Indonesia
Noorwati Sutandyo Haematology and Medical Oncology Department, Dharmais National Cancer Centre Hospital, Jakarta, Indonesia

DOI: https://doi.org/10.22146/inajbcs.v57i3.Supplement.24275

Keywords: Genetic testing, breast cancer, colorectal cancer, MUTYH gene, hereditary cancer

Abstract

The MUTYH gene, an essential component of the base excision repair (BER) pathway, is traditionally linked to MUTYH-associated polyposis (MAP) and colorectal cancer (CRC) predisposition; however, recent findings indicate a wider oncogenic significance, encompassing breast cancer as well. We present a rare germline nonsense variant in the MUTYH gene (c.383G>A; p.Trp128Ter) in a 68-year-old postmenopausal female diagnosed with stage IIIB luminal A breast carcinoma. Histopathological examination revealed grade II solid papillary carcinoma with invasive carcinoma, no special type (NST), and a Ki67 index of 10%, indicative of a low-proliferative yet locally advanced malignancy. Genetic testing using the TruSight Hereditary Cancer Panel (113 genes) verified the presence truncating variant, which is predicted to induce premature protein termination and loss of protein functional. The patient's family history comprised colorectal cancer in her elder sister and thyroid cancer in her father, showing a broader cancer susceptibility linked to MUTYH variants beyond colorectal neoplasia. The identification of a pathogenic truncating MUTYH variant in a luminal A breast cancer patient adds to the mounting evidence associating these mutations to breast cancer risk, particularly in postmenopausal women with hormone receptor–positive subtypes. The p.Trp128Ter mutation appears to affect base excision repair, increasing vulnerability to oxidative DNA damage and genomic instability. This case underscores the pleiotropic function of MUTYH in hereditary cancer syndromes and advocates for its incorporation into multi-cancer genetic panels, regardless of the presence of a conventional MAP phenotype. It further highlights the importance of comprehensive hereditary cancer evaluation, personalised genetic counselling, and long-term family surveillance, as well as the need for ongoing study into MUTYH's role in breast cancer susceptibility.