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Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15497-501. doi: 10.1073/pnas.1417322111. Epub 2014 Oct 13.

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li-Fraumeni cancer predisposition syndrome.

Author information

1
University of Malaya Cancer Research Institute, University of Malaya, 50603 Kuala Lumpur, Malaysia; Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, Malaysia;
2
International Prevention Research Institute, 69006 Lyon, France; Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale 823, University Grenoble-Alpes, 38706 Grenoble, France;
3
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901;
4
Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, Kuala Lumpur, Malaysia;
5
University of Malaya Cancer Research Institute, University of Malaya, 50603 Kuala Lumpur, Malaysia;
6
Department of Oncogenetics, International Research Center, AC Camargo Cancer Center, National Institute of Oncogenomics, 01508-010, Sao Paulo, Brazil;
7
Institute for Advanced Study, Princeton, NJ 08540; and chanc3@cinj.rutgers.edu alevine@ias.edu.
8
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903 chanc3@cinj.rutgers.edu alevine@ias.edu.

Abstract

The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.

KEYWORDS:

Li–Fraumeni syndrome; copy number variation; genetic anticipation; p53 mutation; whole genome sequencing

PMID:
25313051
PMCID:
PMC4217424
DOI:
10.1073/pnas.1417322111
[Indexed for MEDLINE]
Free PMC Article

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