bims-lifras 2024-01-21 papers

Issue of 2024–01–21
five papers selected by
Joanna Zawacka, Karolinska Institutet

Hered Cancer Clin Pract. 2024 Jan 18. 22(1): 1

Li-Fraumeni syndrome presenting with de novo TP53 mutation, severe phenotype and advanced paternal age: a case report.

Juan Pablo Arango-Ibañez, Luis Gabriel Parra-Lara, Ángela R Zambrano, Lisa Ximena Rodríguez-Rojas.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic variants in the gene TP53. This gene codes for the P53 protein, a crucial player in genomic stability, which functions as a tumor suppressor gene. Individuals with LFS frequently develop multiple primary tumors at a young age, such as soft tissue sarcomas, breast cancer, and brain tumors.
CASE PRESENTATION: A 38 years-old female with a history of femur osteosarcoma, ductal carcinoma of the breast, high-grade breast sarcoma, pleomorphic sarcoma of the left upper limb, infiltrating lobular carcinoma of the breast, gastric adenocarcinoma, leiomyosarcoma of the right upper limb, and high-grade pleomorphic renal sarcoma. Complete molecular sequencing of the TP53 gene showed c.586 C > T (p.R196X) in exon 6, which is a nonsense mutation that produces a shorter and malfunctioning P53. Family history includes advanced father's age at the time of conception (75 years), which has been associated with an increased risk of de novo germline mutations. The patient had seven paternal half-siblings with no cancer history. The patient received multiple treatments including surgery, systemic therapy, and radiotherapy, but died at the age of 38.
CONCLUSIONS: Advanced paternal age is a risk factor to consider when hereditary cancer syndrome is suspected. Early detection of hereditary cancer syndromes and their multi-disciplinary surveillance and treatment is important to improve clinical outcomes for these patients. Further investigation of the relationship between the pathogenic variant of TP53 and its phenotype may guide the stratification of surveillance and treatment.

Keywords: Advanced paternal age; De novo mutation; Li Fraumeni syndrome; P53; Severe phenotype; TP53

DOI: https://doi.org/10.1186/s13053-023-00272-2

Cancer Med. 2024 Jan 17.

Phenotype analysis of families with TP53 germline variants at the Center for Familial Breast and Ovarian Cancer, Cologne.

K Kast, K Rhiem, M Larsen, B Wappenschmidt, R Schmutzler.

PURPOSE: Tumor protein p53 (TP53) pathogenic variant (PV) carriers are identified during genetic testing for hereditary causes of cancer. PVs in TP53 are associated with the Li-Fraumeni syndrome (LFS), and thus, surveillance and preventive measures are important for TP53 PV carriers. However, the penetrance of TP53 PVs can be low if the Chompret criteria are not fulfilled. In this study, we compared the phenotypic characteristics of families that did and did not fulfill the LFS criteria according to Chompret.
METHODS: The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) database was used to identify index patients with a likely pathogenic/pathogenic TP53 variant and their family members. The study investigated the type of variant, pedigree, age of onset, number of primary tumors, and histological type of BC.
RESULTS: TP53 PV were present in the index cases of 35 families, 57% (20/35) of which fulfilled the Chompret criteria. The median age of onset at first BC diagnosis was lower in families that fulfilled the Chompret criteria compared to those who did not. Four of all diseased individuals were minors (4%; 4/105) when malignancy was first diagnosed. Sarcomas and brain tumors occurred in 10% (10/105) and in 7% (7/105) of all diseased persons, respectively. BC was the most frequently occurring first tumor (60%; 62/105) and additional malignancy (45%; 20/44) in this cohort. Subsequent malignancies developed in 31% (20/65) of the individuals who fulfilled the Chompret criteria compared with 15% (6/40) of those who did not.
CONCLUSION: The tumor spectrum and age of onset found in this study showed that tumors other than BC had low disease penetrance in TP53 PV carriers identified using the GC-HBOC criteria for genetic testing.

Keywords: breast cancer; cancer prevention; genetic variants; next-generation sequencing

DOI: https://doi.org/10.1002/cam4.6920

Pathol Res Pract. 2024 Jan 02. pii: S0344-0338(23)00776-8. [Epub ahead of print]254 155075

Germline mutational variants of Turkish ovarian cancer patients suspected of Hereditary Breast and Ovarian Cancer (HBOC) by next-generation sequencing.

Seref Bugra Tuncer, Betul Celik, Seda Kilic Erciyas, Ozge Sukruoglu Erdogan, Busra Kurt Gültaslar, Demet Akdeniz Odemis, Mukaddes Avsar, Fatma Sen, Pınar Mualla Saip, Hulya Yazici.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is characterized by an increased risk of developing breast cancer (BC) and ovarian cancer (OC) due to inherited genetic mutations. Understanding the genetic variants associated with HBOC is crucial for identifying individuals at high risk and implementing appropriate preventive measures. The study included 630 Turkish OC patients with confirmed diagnostic criteria of The National Comprehensive Cancer Network (NCCN) concerning HBOC. Genomic DNA was extracted from peripheral blood samples, and targeted Next-generation sequencing (NGS) was performed. Bioinformatics analysis and variant interpretation were conducted to identify pathogenic variants (PVs). Our analysis revealed a spectrum of germline pathogenic variants associated with HBOC in Turkish OC patients. Notably, several pathogenic variants in BRCA1, BRCA2, and other DNA repair genes were identified. Specifically, we observed germline PVs in 130 individuals, accounting for 20.63% of the total cohort. 76 distinct PVs in genes, BRCA1 (40 PVs), BRCA2 (29 PVs), ATM (1 PV), CHEK2 (2 PVs), ERCC2 (1 PV), MUTYH (1 PV), RAD51C (1 PV), and TP53 (1PV) and also, two different PVs (i.e., c.135-2 A>G p.? in BRCA1 and c.6466_6469delTCTC in BRCA2) were detected in a 34-year-old OC patient. In conclusion, our study contributes to a better understanding of the genetic variants underlying HBOC in Turkish OC patients. These findings provide valuable insights into the genetic architecture of HBOC in the Turkish population and shed light on the potential contribution of specific germline PVs to the increased risk of OC.

Keywords: BRCA1/BRCA2; Germline Mutations; HBOC; Multigene panels; NGS; Ovarian cancer

DOI: https://doi.org/10.1016/j.prp.2023.155075

Diagn Pathol. 2024 Jan 19. 19(1): 16

Epithelioid angiomyolipoma of the liver in a patient with Li-Fraumeni syndrome: a case report.

Yaewon Yang, Jisun Lee, Chang Gok Woo, Ok-Jun Lee, Seung-Myoung Son.

BACKGROUND: Epithelioid angiomyolipoma (EAML) is a rare variant of angiomyolipoma that predominantly consists of epithelioid cells and belongs to the perivascular epithelioid cell neoplasm (PEComa) family. The majority of EAMLs arise in the kidneys, and primary hepatic EAML appears to be much less common than renal EAML. Most PEComas arise sporadically, but may be associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder characterized by germline mutations in the TSC1 or TSC2 genes. However, PEComas have previously been reported in five patients with Li-Fraumeni syndrome (LFS), which is an inherited cancer susceptibility disorder resulting from germline mutations in the TP53 tumor suppressor gene.
CASE PRESENTATION: We report a 49-year-old female patient with hepatic EAML and pancreatic cancer. Because she had previously been diagnosed with bilateral breast cancer at the age of 30, we performed a comprehensive genetic analysis to identify genetic alterations associated with any cancer predisposition syndrome. Whole-exome sequencing of a blood sample identified a heterozygous germline variant of TP53 (NM_000546.5):c.708C>A, and targeted next-generation sequencing of liver EAML and pancreatic cancer tissue samples demonstrated the same TP53 (NM_000546.5):c.708C>A variant in both. This, plus the patient's history of early-onset breast cancer, met the 2015 version of the Chompret criteria for diagnosis of LFS.
CONCLUSIONS: There have been very few case reports regarding the presence of PEComa in LFS, and to the best of our knowledge, this is the first report of EAML of the liver in a patient with LFS.

Keywords: Angiomyolipoma; Epithelioid angiomyolipoma; Li-Fraumeni syndrome; PEComa

DOI: https://doi.org/10.1186/s13000-023-01418-5