bims-lifras 2023-07-02 papers

Issue of 2023‒07‒02
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Cancer Res Commun. 2023 May;3(5): 738-754

Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633-0.810).Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.

DOI: https://doi.org/10.1158/2767-9764.CRC-22-0402

Trends Ecol Evol. 2023 Jun 21. pii: S0169-5347(23)00135-0. [Epub ahead of print]

Uncoupling elephant TP53 and cancer.

Fritz Vollrath.

Elephant testicles do not descend, with implications for sperm production being hot enough to compromise germline DNA replication/repair. Uniquely, elephants also possess 20 copies of a gene encoding for the p53 protein. Did elephants evolve multiplication of the TP53 gene complex to protect their germline rather than to fight cancer?

Keywords: Afrotheria; Elephantidae; Loxodonta; Peto’s paradox; TP53 retrogenes; cancer; climate change; germline; p53 isoforms; soma

DOI: https://doi.org/10.1016/j.tree.2023.05.011

Neuro Oncol. 2023 Jun 28. pii: noad114. [Epub ahead of print]

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

Anna S Kolodziejczak, Lea Guerrini-Rousseau, Julien Masliah Planchon, Jonas Ecker, Florian Selt, Martin Mynarek, Denise Obrecht, Martin Sill, Robert J Autry, Eric Zhao, Steffen Hirsch, Elsa Amouyal, Christelle Dufour, Olivier Ayrault, Jacob Torrejon, Sebastian M Waszak, Vijay Ramaswamy, Virve Pentikainen, Haci Ahmet Demir, Steven C Clifford, Ed C Schwalbe, Luca Massimi, Matija Snuderl, Kristyn Galbraith, Matthias A Karajannis, Katherine Hill, Bryan K Li, Mike Walsh, Christine L White, Shelagh Redmond, Loizou Loizos, Marcus Jakob, Uwe R Kordes, Irene Schmid, Julia Hauer, Claudia Blattmann, Maria Filippidou, Gianluca Piccolo, Wolfram Scheurlen, Ahmed Farrag, Kerstin Grund, Christian Sutter, Torsten Pietsch, Stephan Frank, Denis M Schewe, David Malkin, Myriam Ben-Arush, Astrid Sehested, Tai-Tong Wong, Kuo-Sheng Wu, Yen-Lin Liu, Fernando Carceller, Sabine Mueller, Schuyler Stoller, Michael D Taylor, Uri Tabori, Eric Bouffet, Marcel Kool, Felix Sahm, Andreas von Deimling, Andrey Korshunov, Katja von Hoff, Christian P Kratz, Dominik Sturm, David T W Jones, Stefan Rutkowski, Cornelis M van Tilburg, Olaf Witt, Gaëlle Bougeard, Kristian W Pajtler, Stefan M Pfister, Franck Bourdeaut, Till Milde.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.
RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received post-operative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).
CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Keywords: Li-Fraumeni syndrome; TP53; medulloblastoma; survival

DOI: https://doi.org/10.1093/neuonc/noad114

Ann Med Surg (Lond). 2023 Jun;85(6): 3012-3016

Li-Fraumeni syndrome in the setting of re-occurring malignancies after 27 years of remission: a case report.

Ahmed H Mousa, Abdullatif S Ibrahim, Abdelrahman Waleed Alsayed, Zain Z Albukhari, Ajfan Mogharbel, Asim M Alshanberi, Nezar Y Albar.

Multiple primary tumors are defined as multiple simultaneous (within 6 months) or heterogeneous tumors.Case presentation: Here, the authors present the case of a 58-year-old Saudi female patient with Li-Fraumeni syndrome who has multiple primary tumors.
Clinical discussion: The surgical cytoreduction or 'debulking' technique is the main treatment option started in individuals with High Grade Serous Ovarian CanceR. This surgical strategy aims to completely remove all disseminated tumor masses that are present in the patient's peritoneal cavity on a macroscopic level.
Conclusion: In conclusion, in our case, she has developed her ovarian cancer 27 years after her breast cancer got treated. This was already stage IIIB to stage IV. If it was not for her incidental discovery of her urinary bladder cancer, which is most likely is a long-term sequel of using cyclophosphamide 27 years ago.Multiple primary tumors are defined as multiple simultaneous (within 6 months) or heterogeneous tumors. Here, the authors present the case of a 58-year-old Saudi female patient with Li-Fraumeni syndrome who has multiple primary tumors. In conclusion, in our case, she has developed her ovarian cancer 27 years after her breast cancer got treated. This was already stage IIIB to stage IV. If it was not for her incidental discovery of her urinary bladder cancer, which is most likely is a long-term sequel of using cyclophosphamide 27 years ago.

Keywords: Li-Fraumeni syndrome; cancer; malignancies; oncology

DOI: https://doi.org/10.1097/MS9.0000000000000724

Ecancermedicalscience. 2023 ;17 1550

Lessons learnt from the clinico-genomic profiling of families with Li Fraumeni syndrome at a tertiary care centre in North India.

Ghazal Tansir, Sameer Rastogi, Sravan Kumar Dubasi, Sindhu Chitikela, Lavu Rohit Reddy, Adarsh Barwad, Ankur Goyal.

Li Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome due to TP53 gene mutation. There is sparse literature on LFS in the Indian population. We conducted a retrospective study of patients diagnosed with LFS and their family members, registered at our Medical Oncology Department between September 2015 and 2022. 9 LFS families consisted of 29 patients diagnosed currently or historically with malignancies including 9 index cases and 20 first or second-degree relatives. Of these 29 patients, 7 (24.1%) patients developed their first malignancy before the age of 18 years, 15 (51.7%) were diagnosed between 18and and 60 years, and 7 (24.1%) were diagnosed at age more than 60 years. A total of 31 cancers occurred among the families, including 2 index cases who had metachronous malignancies. Each family had a median of three cancers (range 2-5); sarcoma (n = 12, 38.7% of total cancers) and breast cancer (n = 6, 19.3% of total cancers) being the commonest malignancies. Germline TP53 mutations were documented among 11 patients with cancers and 6 asymptomatic carriers. Of these nine mutations, the most common types were missense (n = 6, 66.6%) and nonsense (n = 2, 22.2%), and the commonest aberration was replacement of arginine with histidine (n = 4, 44.4%). Eight (88.8%) families met either classical or Chompret's diagnostic criteria and two (22.2%) satisfied both. Two (22.2%) families fit the diagnostic criteria prior to onset of malignancy in the index cases but were untested till the index cases presented to us. Four mutation carriers from three families are undergoing screening as per the Toronto protocol. No new malignancies have been detected so far during the mean surveillance duration of 14 months. The diagnosis of LFS has socio-economic implications for patients and their families. Delay in genetic testing misses out a crucial window wherein asymptomatic carriers could initiate surveillance in a timely fashion. Greater awareness on LFS and genetic testing in Indian patients is warranted for better management of this hereditary condition.

Keywords: genetic counselling; genetic syndromes; hereditary cancers; sarcoma

DOI: https://doi.org/10.3332/ecancer.2023.1550

Cancers (Basel). 2023 Jun 16. pii: 3210. [Epub ahead of print]15(12):

TP53 Mutations in AML Patients Are Associated with Dismal Clinical Outcome Irrespective of Frontline Induction Regimen and Allogeneic Hematopoietic Cell Transplantation.

Davidson Zhao, Mojgan Zarif, Qianghua Zhou, José-Mario Capo-Chichi, Andre Schuh, Mark D Minden, Eshetu G Atenafu, Rajat Kumar, Hong Chang.

TP53 mutations are associated with extremely poor outcomes in acute myeloid leukemia (AML). The outcomes of patients with TP53-mutated (TP53MUT) AML after different frontline treatment modalities are not well established. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for AML; however, long-term outcomes among patients with TP53MUT AML after allo-HCT are dismal, and the benefit of allo-HCT remains controversial. We sought to evaluate the outcomes of patients with TP53MUT AML after treatment with different frontline induction therapies and allo-HCT. A total of 113 patients with TP53MUT AML were retrospectively evaluated. Patients with TP53MUT AML who received intensive or azacitidine-venetoclax induction had higher complete remission rates compared to patients treated with other hypomethylating-agent-based induction regimens. However, OS and EFS were not significantly different among the induction regimen groups. Allo-HCT was associated with improved OS and EFS among patients with TP53MUT AML; however, allo-HCT was not significantly associated with improved OS or EFS in time-dependent or landmark analysis. While the outcomes of all patients were generally poor irrespective of therapeutic strategy, transplanted patients with lower TP53MUT variant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higher TP53 VAF. Our study provides further evidence that the current standards of care for AML confer limited therapeutic benefit to patients with TP53 mutations.

Keywords: AML; TP53; next-generation sequencing; transplantation

DOI: https://doi.org/10.3390/cancers15123210