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

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.Li-Fraumeni syndrome | whole genome sequencing | genetic anticipation | p53 mutation | copy number variation

The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation

“…Alternatively, there may be some rare alleles in other genes that back up p53 function. As discussed above, the loss of the p53 protein does not appear to increase genomic instability in the germline of Li -Fraumeni patients nor in mice that are bred from p53-null parents (Ariffin et al 2014). This suggests that anticipation observed in Li -Fraumeni families (a lower age of onset of tumor development in successive generations of a family) is not a result of genomic instability in the germline.…”

“…DNA sequencing of blood samples from family members carrying p53 mutations or family members with wild-type p53 genes over two generations in a Li -Fraumeni family with anticipation (a lowering of the age of onset of the first tumor) failed to show any increase in CNVs over subsequent generations when comparing individuals with two copies of wild-type p53 with those with one copy (Ariffin et al 2014). Both the results from mice and the results from humans have failed to show that p53 has a role in protecting genome stability in the germline in mammals as it and/or its family members do in invertebrates (Ariffin et al 2014). p63, however, does enforce germline genome stability in females (Suh et al 2006).…”

“…With some inherited neurological diseases, an earlier onset of symptoms (anticipation) in the younger generation is accompanied by an increase in a G/C-rich trinucleotide repeat 5 0 to the gene or in the protein. This is not the case for the p53 mutant gene in Li -Fraumeni syndrome (Ariffin et al 2014). A tempting hypothesis is that the p53 protein plays a role in the germline similar to its function in the somatic tissues, it protects against genomic instability, killing cells that undergo such changes in the genome.…”

Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p

“…After genotypes were established, haplotype frequencies were estimated using the ARLEQUIN v3.5 software [ 27 ] in 500 chromosomes from unrelated control individuals from Porto Alegre, 540 chromosomes from unrelated Portuguese individuals, 240 chromosomes from unrelated African individuals and 200 chromosomes from Native American individuals. ARLEQUIN v3.5 was also used to compare the ancestral haplotype in which the p.Arg337His mutation is present with the constructed parental population haplotypes, assuming that the most likely parental population would present the least average pairwise difference with the ancestral haplotype in which the p.Arg337His mutation is present [ 28 , 29 ].…”

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect

“…A recent whole-genome sequencing study of germline DNA in 13 Li-Fraumeni syndrome cases did not find increased DNA copynumber variations, suggesting that CNVs do not mediate the genetic anticipation effect. The authors proposed an alternative model explaining apparent anticipation in which variants from the noncarrier parent influence tumorigenesis in the offspring of TP53 mutation carriers with late onset of cancer (21). In other words, parents with relatively late onset might have offspring that are more prone to tumorigenesis due to inheritance of specific risk increasing variants from the noncarrier parent.…”