Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1

作者：Aaron Seo, Orna Steinberg‐Shemer, Şule Ünal, Silvia Casadei, Tom Walsh, Fatma Gümrük, Stavit A. Shalev, Akiko Shimamura, Nurten Akarsu, Hannah Tamary, Mary‐Claire King · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · 被引用次数：47 · 研究领域：BRCA gene mutations in cancer、DNA Repair Mechanisms、Genetic factors in colorectal cancer

Significance Many patients with breast and ovarian cancer carry inherited cancer-predisposing mutations in BRCA1 . However, virtually no patients have two inherited mutations in BRCA1 because the DNA repair function of BRCA1 is essential for embryonic development. We discovered that patients with two nonsense mutations from a specific region of BRCA1 may survive as the result of naturally occurring alternative splicing that yields a short but partially functional BRCA1 protein. These patients are extremely rare, and are characterized by severe chromosomal fragility, congenital anomalies, and predisposition to childhood cancers.