Ann Lab Med.  2013 May;33(3):212-216. 10.3343/alm.2013.33.3.212.

A Case of Late-Onset Li-Fraumeni-like Syndrome with Unilateral Breast Cancer

• Cho Y
• Kim J
• Kim Y
• Jeong J
• Lee KA

• KMID: 1781330
• DOI: http://doi.org/10.3343/alm.2013.33.3.212

Abstract

Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.

Keyword

Li-Fraumeni syndrome; LFS; Li-Fraumeni-like syndrome; LFL; TP53; Breast cancer; Late onset; Penetrance

MeSH Terms

Adolescent
Adult
Breast Neoplasms/complications/*diagnosis/therapy
Combined Modality Therapy
Exons
Female
Genotype
Heterozygote
Humans
Li-Fraumeni Syndrome/complications/*diagnosis/therapy
Middle Aged
Multimodal Imaging
Mutation, Missense
Pedigree
Sequence Analysis, DNA
Tumor Suppressor Protein p53/genetics
Young Adult
Tumor Suppressor Protein p53

Figure

• 

  Fig. 1 Pedigree of the TP53 A189V family. Generations are in Roman numerals and individuals are in Arabic numbers (without parenthesis). Individuals with a clinical diagnosis of a cancer are presented with a solid symbol and a footnote regarding the specific cancer type (age of onset). Individuals without a history of cancer are presented with open symbols. The proband is marked by an arrow.Abbreviation: IDC, invasive ductal carcinoma.

• 

  Fig. 2 Nucleotide sequence analysis of the TP53 gene of family members. DNA-segments include the coding sequence 566 of the TP53 gene (marked by black arrows). The patient had a compound heterozygous missense mutation in exon 6 (c.566C>T; p.Ala189Val) and IDC tissue was homozygous for the mutation. The patient's 2 daughters (III-1 and III-2) were found to be heterozygous carriers for the mutation, whereas the patient's son (III-3) had a wild type TP53 gene.Abbreviations: PB, peripheral blood; IDC, invasive ductal carcinoma.

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