Case Report: Germline LZTR1 loss-of-function mutation in high-grade serous ovarian cancer with a three-generation family history of malignancy

Hereditary predisposition plays a critical role in ovarian cancer etiology, yet many cases remain unexplained by BRCA1/2 mutations. Leucine zipper-like transcriptional regulator 1 ( LZTR1 ) encodes a Cullin3 E3 ubiquitin ligase adaptor mediating RAS ubiquitination and degradation; its germline mutations predispose to schwannomatosis and Noonan syndrome, with tumor-suppressive functions demonstrated in glioblastoma, but no association with ovarian cancer has been reported. We present a 68-year-old woman with stage IVB high-grade serous ovarian cancer (HGSC) whose whole exome sequencing revealed a germline LZTR1 frameshift mutation (c.27dupG, p.Q10fs) with loss of heterozygosity, wild-type BRCA1/2 , and homologous recombination deficiency (HRD)-positive status with a genomic instability score of 67. Her three-generation pedigree included breast cancer (daughter, age 32), gastric adenocarcinoma (father), and hepatocellular carcinoma (mother). Sanger sequencing confirmed the identical heterozygous LZTR1 mutation in two unaffected sisters. Following neoadjuvant chemotherapy and interval debulking surgery, the patient achieved near-complete pathological response and remains disease-free at 29 months on poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy. This is the first report of HGSC harboring a germline LZTR1 loss-of-function mutation with a three-generation family history of malignancy. The co-occurrence of LZTR1 inactivation with HRD-positive and BRCA wild-type status raises the possibility of a mechanistic link warranting investigation; however, whether the loss of LZTR1 contributed to HRD remains unknown. This case warrants further evaluation of LZTR1 in expanded genetic testing panels for hereditary cancer-predisposing syndromes.