Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder associated with an increased risk of developing various cancers from childhood. Various studies and efforts are ongoing to enable earlier detection and prevention of LFS tumors, further optimization of surveillance with better sensitivity and less burden for patients, and better quality of life for patients and family members. Here, we introduce updates on recent LFS research, including the discussion in the LFS association meeting in 2024. With this review, we hope to provide medical providers, patients, and their family members with a brief overview of current LFS research and insights into future directions.

　With the widespread use of next-generation sequencing, detecting two pathogenic variants at two loci in an individual is often incidental. A 72-year-old woman was diagnosed with early breast cancer. Her mother, sister, and two maternal aunts displayed histories of breast cancer as well. A preoperative CT scan revealed multiple shunts in the liver of the patient. Moreover, beyond repeated epistaxis and the oral mucosa-related results, we diagnosed the patient with Osler-Weber-Rendu disease and a heterozygous ACVRL1 mutation. Postoperatively, the patient wanted to undergo BRCA1 and BRCA2 genetic testing, which revealed a heterozygous BRCA2 mutation, leading to a diagnosis of hereditary breast and ovarian cancer. Later, the patient received genetic counseling (GC) for the two genetic disorders in separate sessions. We diagnosed the patient with two hereditary disorders based on the phenotype within a short period after having suffered breast cancer. The objective of GC is to help clients understand their condition without confusion.

　Background: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited multiorgan disease. Herein, we describe a sporadic case of BHDS confirmed by genomic testing whose pulmonary cysts revealed characteristic features on radiological and pathological examination. 　Case presentation: A 57-year-old male with past history of repeated bilateral pneumothorax revisited our hospital complaining of right chest pain. He had no familial history of pneumothorax. 　Chest computed tomography revealed pneumothorax in his right chest. Multiple irregular-shaped cysts from 5 mm to 30 mm in diameter were observed predominantly in the lower and medial region of bilateral lungs. After conservative treatment with chest tube drainage, the patient underwent video-assisted thoraco-surgery. Then our pathologist identified characteristic microscopical findings associated with BHDS in which there were less inflammatory reaction and less fibrosis beside cyst wall than in emphysematous cysts. Additionally, Elastica van Gieson stain revealed that the continuity of the elastic tissue on the cyst wall was relatively maintained in comparison to the emphysematous cysts. BHDS was strongly suspected and whole exome analysis of FLCN gene was performed. Finally, it revealed pathogenic variant, NM_144997.7:c.1347_1353dup (p.Val452fs) on the exon 12. 　We recommended surveillance with contrast-enhanced renal magnetic resonance imaging and consultation to our dermatologist to the patient. Renal MRI revealed hypo-vascular tiny round solid tumor (6 mm diameter) on left kidney. 　Conclusions: Recognition of typical imaging and characteristic pathological findings are crucial to diagnose BHDS and to inform suitable surveillance strategies for patients and their relatives promptly.

　The patient was a 52-year-old woman who was found to be BRCA1 pathogenic variant-positive during treatment for ovarian cancer. After her ovarian cancer condition stabilized, breast cancer surveillance, including contrast-enhanced breast MRI was performed. She was subsequently diagnosed with DCIS following an MRI-guided biopsy. It is necessary to conduct appropriate breast cancer surveillance for ovarian cancer patients with BRCA1/2 pathogenic variants and to consider treatment and risk-reducing surgery based on the condition.

　A 51-year-old woman was admitted to our hospital with a complaint of a right axillary mass. Examination revealed right axillary lymph node enlargement, and chest and abdominal contrast-enhanced CT and PET-CT scans demonstrated FDG accumulation in the enlarged right axillary lymph node. A needle biopsy of this lymph node confirmed the presence of a malignant epithelial tumor of breast origin. However, visual and palpable examinations, along with mammography (MMG), ultrasound (US), and contrast-enhanced MRI, did not reveal any obvious abnormalities in either breast, leading to a diagnosis of occult breast cancer. Right axillary lymph node dissection was performed without breast resection, and pathological examination revealed lymph node metastasis from breast cancer, classified as pT0, pN3a, M0, Stage IIIc, with HER2 (1+), ER (+), PgR (+), and a MIB-1 index of 73.5%. The patient subsequently received adjuvant chemotherapy, radiotherapy, and endocrine therapy, with no evidence of recurrence to date. During follow-up, hereditary breast and ovarian cancer (HBOC) genetic testing was covered by insurance. The genetic testing revealed a positive BRCA2 pathogenic variant. We report this rare case of occult breast cancer with a pathogenic BRCA2 variant, accompanied by a review of the relevant literature.

　Breast cancer is frequently diagnosed in women of reproductive age, and for those who wish to have children, consideration of fertility preservation prior to the initiation of cancer treatment is essential. When hereditary breast and ovarian cancer (HBOC) is identified at the time of breast cancer diagnosis, patients are confronted with multiple challenges-including cancer disclosure, treatment decisions, genetic counseling, and fertility preservation-within a limited timeframe. We report a case in which HBOC was diagnosed concurrently with breast cancer, and the patient’s intention regarding fertility preservation changed before and after the initiation of cancer treatment. This case highlights the ethical challenges associated with fertility preservation in HBOC and discusses optimal strategies for supporting patient decision-making.

　A 66-year-old woman had undergone partial mastectomy and sentinel node biopsy for right breast cancer at age 48, followed by adjuvant chemotherapy and radiotherapy for stage I triple-negative breast cancer. Due to a family history of breast cancer (maternal grandmother and a cousin), germline BRCA1/2 genetic testing was performed, revealing the BRCA2 c.7847C>T (p.Ser2616Phe) variant, classified as a variant of uncertain significance (VUS). Based on database reviews and in silico analyses, hereditary breast and ovarian cancer (HBOC) was suspected. Annual mammography was continued after 10 years postoperatively, with a contralateral left breast mass detected 18 years postoperatively. Left breast cancer was diagnosed, and mastectomy with sentinel lymph node biopsy was performed; the final diagnosis was ductal carcinoma in situ. Although classified as VUS, previous reports suggested this variant may be pathogenic, potentially warranting reclassification. Continued monitoring and appropriate measurement will be provided.

　Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome caused by pathogenic variants in the TP53 gene. Although difficult to diagnose, suspected cases have been increasing in recent years. In this case, LFS was suspected based on the client’s personal and family history. The NCC OncoPanel test, a form of comprehensive genomic profiling (CGP) primarily used to identify therapeutic targets, was performed with the client’s consent. No germline pathogenic variant in TP53 was detected. However, careful review of supplementary data suggested a large germline deletion. Additional genetic testing confirmed the diagnosis of LFS. 　Throughout the diagnostic process, the client experienced psychological distress and was supported through multiple genetic counseling sessions. However, the client ultimately passed away while still harboring strong concerns for their relatives. 　This report discusses the process leading to the definitive diagnosis, the contributions of genetic counseling.