The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families
Introduction
Li-Fraumeni syndrome (LFS; OMIM no. 151623) is a clinically defined syndrome characterized by early onset soft tissue sarcomas (STS) and bone sarcomas (BoneS), associated with other early onset cancers. The most frequent associated cancers include breast cancers (BC), brain tumours (BT) and adrenal cortical carcinomas (ADR), but a wide range of less frequent cancers are also observed such as lymphomas, lung cancer, gastric cancer, cancers of the female genital organs and melanoma [1], [2], [3]. Families with incomplete features of LFS are referred to as Li-Fraumeni-like (LFL) syndrome for which several clinical definitions have been proposed (LFL-B [4], LFL-E1 and LFL-E2 [5]).
Germline mutations in the tumour suppressor gene TP53 (chromosome 17p13; OMIM no. 191170) have been found in 70% of LFS cases and 40% of LFL cases [4], [6]. TP53 encodes a transcription factor, p53, involved in many overlapping cellular pathways that control cell proliferation, cell survival and genomic integrity, and is often inactivated by somatic mutations in cancers [7]. Over 280 germline mutations have been reported and compiled in the IARC TP53 database (http://www-p53.iarc.fr/Germline.html). Their type and distribution are very similar to somatic TP53 mutations, with a majority of missense mutations affecting the DNA-binding domain of the protein [8]. Recently, a germline mutation affecting the oligomerisation domain of p53, R337H (CGC to CAC at codon 337 in exon 10), has been reported in Brazilian children with ADR but no documented familial history of other cancers [9], [10]. This situation is unique in the TP53 mutation spectrum because so far no other germline mutation has been reported to predispose exclusively to one type of cancer. A structural hypothesis has been put forward to account for this tissue specificity. Arginine 337 is located in the dimerisation motif of the p53 protein and its replacement by histidine alters hydrogen bonding between two p53 monomers and hampers dimerisation in a pH-dependent manner [11]. Failure to make proper oligomers inactivates the capacity to bind with high affinity to p53-response elements, a property essential to transactivation of p53 target genes. This observation has led to speculate that R337H may have a narrow spectrum of effects, restricted to tissues where variations in intracellular pH constitute growth or survival regulatory signals. Why this would be the case in adrenal cortical glands, and not in other tissues, is not understood.
Section snippets
Methods
Forty-five families with cancer histories matching the classical clinical definition of Li-Fraumeni syndrome (LFS [1]) or one of the Li-Fraumeni like definitions (LFL-B [12], LFL-E1 and LFL-E2 [13], [14]) were identified at the Department of Oncogenetics, Hospital AC Camargo in São Paulo (32 families), the Serviço de Genética Médica, Hospital das Clínicas in Porto Alegre (10 families) and the Instituto Nacional do Câncer (INCA) in Rio de Janeiro (three families). All family members have been
Results
In this study, we have screened TP53 germline mutations in 45 unrelated Brazilian subjects, whose family histories matched LFS or LFL clinical definitions, to characterise the prevalence and type of TP53 mutations associated with these syndromes in the Brazilian population. In 32 index cases, no TP53 mutation could be detected by sequencing (Table s1). In 13 index cases, a single mutation was found. The mutations and the clinical characteristics of these families are detailed in Table 1.
All TP53
Discussion
This study is the first description of the prevalence of TP53 germline mutations in families from Latin America that match the clinical definitions of LFS or LFL syndromes. The families were selected from major cancer centres in Brazil, operating as tertiary referral centres for many of familial cancer cases detected in the Brazilian population. We show that the R337H mutation accounted for half of LFS/LFL families that carry a TP53 mutation in the families under study. Testing of control
Acknowledgements
The authors wish to thank Drs Soares, Isabella Werneck and C. Gallo for stimulating discussions and Dr JY Scoazec for the pathological review of the Y27 breast tumour sample. The work of MIWA at IARC was partially supported by an ICRETT fellowship of Union Internationale Contre le Cancer (UICC), No. 978/2004, and by FAPESP grant No. 03/10121-8. PAP received post-doctoral grants from FAPERGS (99/2009.9), CNPq (301033-99.4) and APES, Brazil (Prodoc 202/03-7). RG receives a research productivity
References (20)
- et al.
Single-step separation of red blood cells. Granulocytes and mononuclear leukocytes on discontinuous density gradients of Ficoll-Hypaque
J. Immunol. Methods
(1974) - et al.
Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors
Am. J. Hum. Genet.
(1999) - et al.
Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome
J. Natl Cancer Inst.
(1969) - et al.
Relative frequency and morphology of cancers in carriers of germline TP53 mutations
Oncogene
(2001) - et al.
Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers
Cancer Epidemiol. Biomarkers Prev.
(2001) - et al.
Prevalence and diversity of constitutional mutations in the p53 gene among 21 li-fraumeni families
Cancer Res.
(1994) Germline mutations in the TP53 gene
Cancer Surv.
(1995)- et al.
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms
Science
(1990) - et al.
Surfing the p53 network
Nature
(2000) - et al.
Li-fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype
Cancer Res.
(2003)
Cited by (156)
First live birth after uterine transposition
2023, Fertility and SterilityThree Primary Tumors Including EGFR-mutated Non–Small Cell Lung Cancer as First Presentation in Patient With Li-Fraumeni Syndrome
2021, Clinical Lung CancerCitation Excerpt :This TP53 mutation subtype is present at an unusually high rate of 0.3% of individuals from southern Brazil where it is associated with a 10 to 15 times greater incidence of pediatric adrenocortical carcinomas.15,16 In 45 unrelated Brazilian individuals with family histories fulfilling classic LFS criteria (Figure 4), 13 patients (28.8%) had TP53 mutations, of whom 6 (46.1%) were R337H.17 Carriers of TP53 R337H mutation differ in their clinical presentation with a 50% to 60% lifetime risk for cancer,18 and penetrance of cancer before age 30 is 15% to 20% compared with 50% in carriers of classic mutation.19