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.

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

Fig. 1.

Pedigree of LFS kindred KA. I:2 and II:2 had breast cancer at ages 38 y and 26 y, respectively. II:5 developed osteosarcoma at age 26 y. III:1 presented at 8 mo with embryonal rhabdomyosarcoma of the trunk. III:4 developed adrenocortical carcinoma (ACC) at 6 mo. There was no reported cancer history for II:1 and his parents and siblings. All members with validated mutation in TP53 are denoted with a dot. The family members II:1, II:2, III:1 to III:6, II:4, II:5, II:8, and III:7 and III:8 were selected for WGS, and II:1, II:2, III:2, III:4, and III:6 were also selected for aCGH.

Fig. 2.

Pedigree of LFL kindred MM. Proband (III:4) was diagnosed with rhabdomyosarcoma at the age of 29 mo. III:2 had succumbed to a brain tumor at age of 32 mo. I:1 died at 55 y of age from breast cancer. The remaining family members are cancer-free. All members with validated mutation in TP53 are denoted with a dot. The family members II:6, II:7, III:1, III:3, and III:4 were selected for WES and aCGH.