bims-lifras 2023-06-25 papers

J Natl Cancer Inst. 2023 Jun 23. pii: djad106. [Epub ahead of print]

Emerging insights into ethnic-specific TP53 germline variants.

Nicholas W Fischer, Yu-Heng Vivian Ma, Jean Gariépy.

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge as they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations based on our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations, their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools are now rapidly improving our understanding of the cancer susceptibility spectrum, leading towards more accurate and personalized cancer risk assessments.

Keywords: TP53 ; Li-Fraumeni Syndrome; SNP; VUS; cancer predisposition; ethnic-specific variants; functional genomics; low penetrance; mutant p53

DOI: https://doi.org/10.1093/jnci/djad106

BMC Womens Health. 2023 06 21. 23(1): 329

First case of endometrial cancer after yolk sac tumor in a patient with Li-Fraumeni syndrome.

Qiu-Lin Ye, Yue Qi, Juan-Juan Liu, Yue-Xin Hu, Yuan Lv, Bei Lin.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease with high penetrance caused by a germline variant of TP53 gene. We report the first case of endometrial cancer after yolk sac tumor with LFS.CASE PRESENTATION: The presented female patient underwent right adnexectomy at age 23 because of a yolk sac tumor of the ovary. At the age of 27, the patient was diagnosed with endometrial adenocarcinoma, received cytoreductive surgery and chemotherapy. Given that her personal cancer history along with a strong family history of cancer, her father passing away from lung cancer at age 48 and her grandmother dying of ovarian cancer at age 50, the patient was referred for genetic counseling and testing. Genetic screening revealed a heterozygous pathogenic TP53 c.844C > T, p.( R282 W) with NM_000546.5 variant, a class 5 (C5) variant. This is the first reported case of a yolk sac tumor accompanied by subsequent endometrial cancer that is associated with LFS.
CONCLUSIONS: We reported a first case of an endometrial cancer after yolk sac tumor patient with a tumor family history of harboring the germline TP53 pathogenic variation which expanded types of tumor that can be presented in patients with LFS. This case highlights the importance of genetic testing for patients with malignant tumors, as well as patients with a family history of malignant tumors. And our case highlights the necessity of screening for gynecologic tumor in LFS patients.

Keywords: Endometrial cancer; Li-Fraumeni syndrome; TP53; Yolk sac tumor

DOI: https://doi.org/10.1186/s12905-023-02426-9

Fam Cancer. 2023 Jun 23.

Willingness of individuals with Li-Fraumeni syndrome to participate in a cancer prevention trial: a survey study.

Farina J Struewe, Sarah Schott, Martina de Zwaan, Christian P Kratz.

DOI: https://doi.org/10.1007/s10689-023-00339-y

J Pathol. 2023 Jun 22.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: ATM; DNA; cancer; immunohistochemistry; inherited; pancreatic; pathogenic; sequencing; somatic; variant

DOI: https://doi.org/10.1002/path.6136