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

Overview

Journal Cancer Res Commun

Specialty Oncology

Date 2023 Jun 28

PMID 37377903

Authors

Vallijah Subasri

Nicholas Light

Nisha Kanwar

Jack Brzezinski

Ping Luo

Jordan R Hansford

Elizabeth Cairney

Carol Portwine

Christine Elser

Jonathan L Finlay

Kim E Nichols

Noa Alon

Ledia Brunga

Jo Anson

Wendy Kohlmann

Kelvin C de Andrade

Payal P Khincha

Sharon A Savage

Joshua D Schiffman

Rosanna Weksberg

Trevor J Pugh

Anita Villani

Adam Shlien

Anna Goldenberg

David Malkin

Affiliations

Soon will be listed here.

Abstract

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 . 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.

Citing Articles

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References

Zhu M, Need A, Han Y, Ge D, Maia J, Zhu Q . Using ERDS to infer copy-number variants in high-coverage genomes. Am J Hum Genet. 2012; 91(3):408-21. PMC: 3511991. DOI: 10.1016/j.ajhg.2012.07.004. View

Zhang J, Walsh M, Wu G, Edmonson M, Gruber T, Easton J . Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015; 373(24):2336-2346. PMC: 4734119. DOI: 10.1056/NEJMoa1508054. View

Charlton J, Williams R, Weeks M, Sebire N, Popov S, Vujanic G . Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood. Genome Biol. 2014; 15(8):434. PMC: 4310621. DOI: 10.1186/s13059-014-0434-y. View

Merino D, Shlien A, Villani A, Pienkowska M, Mack S, Ramaswamy V . Molecular characterization of choroid plexus tumors reveals novel clinically relevant subgroups. Clin Cancer Res. 2014; 21(1):184-92. DOI: 10.1158/1078-0432.CCR-14-1324. View

Stegle O, Parts L, Piipari M, Winn J, Durbin R . Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nat Protoc. 2012; 7(3):500-7. PMC: 3398141. DOI: 10.1038/nprot.2011.457. View

Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L . Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet. 2005; 43(6):531-3. PMC: 1904480. DOI: 10.1136/jmg.2005.037952. View

BELL D, Varley J, Szydlo T, Kang D, Wahrer D, Shannon K . Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 2000; 286(5449):2528-31. DOI: 10.1126/science.286.5449.2528. View

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

Pienkowska M, Choufani S, Turinsky A, Guha T, Merino D, Novokmet A . DNA methylation signature is prognostic of choroid plexus tumor aggressiveness. Clin Epigenetics. 2019; 11(1):117. PMC: 6692938. DOI: 10.1186/s13148-019-0708-z. View

10.

Said B, Malkin D . A functional variant in miR-605 modifies the age of onset in Li-Fraumeni syndrome. Cancer Genet. 2015; 208(1-2):47-51. DOI: 10.1016/j.cancergen.2014.12.003. View

11.

Rausch T, Zichner T, Schlattl A, Stutz A, Benes V, Korbel J . DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012; 28(18):i333-i339. PMC: 3436805. DOI: 10.1093/bioinformatics/bts378. View

12.

Eichler E, Flint J, Gibson G, Kong A, Leal S, Moore J . Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010; 11(6):446-50. PMC: 2942068. DOI: 10.1038/nrg2809. View

13.

Brown N, Bhatia K, Teague J, White S, Lo P, Challis J . Report of a bi-allelic truncating germline mutation in TP53. Fam Cancer. 2018; 18(1):101-104. DOI: 10.1007/s10689-018-0087-1. View

14.

Andrade R, Dos Santos A, de Aguirre Neto J, Nevado J, Lapunzina P, Vargas F . TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes. Fam Cancer. 2016; 16(2):243-248. DOI: 10.1007/s10689-016-9935-z. View

15.

Mai P, Best A, Peters J, DeCastro R, Khincha P, Loud J . Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016; 122(23):3673-3681. PMC: 5115949. DOI: 10.1002/cncr.30248. View

16.

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

17.

Houlahan K, Shiah Y, Gusev A, Yuan J, Ahmed M, Shetty A . Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nat Med. 2019; 25(10):1615-1626. PMC: 7418214. DOI: 10.1038/s41591-019-0579-z. View

18.

Hao Y, Lafita-Navarro M, Zacharias L, Borenstein-Auerbach N, Kim M, Barnes S . Induction of LEF1 by MYC activates the WNT pathway and maintains cell proliferation. Cell Commun Signal. 2019; 17(1):129. PMC: 6798382. DOI: 10.1186/s12964-019-0444-1. View

19.

Bardeesy N, Falkoff D, Petruzzi M, Nowak N, Zabel B, Adam M . Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet. 1994; 7(1):91-7. DOI: 10.1038/ng0594-91. View

20.

Silva A, Ewald I, Sapienza M, Pinheiro M, Peixoto A, Franca de Nobrega A . Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion. BMC Cancer. 2012; 12:237. PMC: 3502571. DOI: 10.1186/1471-2407-12-237. View