eFigure 1. Pedigree of Family 2 affected by the germline TP53 p.R337H mutation
eFigure 2. Pedigree of Family 1 affected by the germline TP53 p.R337H mutation
eFigure 3. Pedigree of Family 4 affected by the germline TP53 p.R337H mutation
eFigure 4. Pedigree of Family 3 affected by the germline TP53 p.R337H mutation
Formiga MNDC, de Andrade KC, Kowalski LP, Achatz MI. Frequency of Thyroid Carcinoma in Brazilian TP53 p.R337H Carriers With Li Fraumeni Syndrome . JAMA Oncol. Published online January 19, 2017. doi:10.1001/jamaoncol.2016.6389
Is thyroid carcinoma related to Li Fraumeni syndrome?
In this cohort of 193 Brazilian patients with Li Fraumeni syndrome carrying the founder TP53 p.R337H mutation, thyroid carcinoma was observed in 11 of 101 cancer-affected patients.
Thyroid carcinoma is a frequent cancer in TP53 p.R337H mutation carriers, suggesting the need to include thyroid imaging in Li Fraumeni syndrome screening protocol.
Li Fraumeni syndrome (LFS) is associated with a wide variety of tumors; nevertheless, thyroid carcinoma has not been evaluated in this syndrome. Due to the Brazilian founder mutation p.R337H, some tumors that have not been described in the classic LFS have been observed in a higher-than-expected prevalence in Brazil.
To determine the frequency of thyroid carcinoma in Brazilian carriers of a founder TP53 p.R337H mutation.
Design, Setting, and Participants
We reviewed medical records of patients with LFS with germline TP53 p.R337H mutation. For a better understanding of the correlation between thyroid carcinoma and LFS, tumor profile data of Brazilian carriers were analyzed. We included data from 193 patients with LFS with the TP53 p.R337H mutation from the database of the Department of Oncogenetics from the A.C. Camargo Cancer Center.
Main Outcomes and Measures
Thyroid tumors found in this population were reviewed with regard to age at diagnosis, sex, histologic subtype, and other tumors presented by these patients.
Overall, 101 of 193 TP53 p.R337H mutation carriers with LFS from 58 families were cancer affected and, among them, thyroid carcinoma presented a prevalence of 10.9% (3 men and 8 women). The mean age at diagnosis was 44 years (median [SD], 43 [14.77] years). All the cases were histologically classified as papillary carcinomas, with 2 of them exhibiting follicular variant. The most common other cancers in the patients with thyroid carcinoma were breast cancer (5 patients) and soft-tissue sarcoma (2 patients).
Conclusions and Relevance
Thyroid carcinoma may be associated with the Brazilian founder TP53 p.R337H mutation. Knowledge about this genotype/phenotype correlation is relevant to adjusting the LFS screening recommendations to these specific carriers.
Li Fraumeni syndrome (LFS) (OMIM 151623) is a rare autosomal-dominant genetic disorder inherited by means of germline TP53 mutations. Carriers have a high lifetime risk of developing multiple early-onset childhood and adult cancers, including soft-tissue and bone sarcomas, central nervous system tumors, adrenocortical tumors, breast cancer, and leukemia.1 In a recent large French series, 332 of 415 carriers were cancer affected and the more prevalent tumors were breast carcinoma (31.1%), soft-tissue sarcoma (18.8%), osteosarcoma (9.6%), central nervous system tumor (7.7%), and adrenocortical carcinoma (7.7%).2
It has been observed that there is substantial clinical tumor heterogeneity in LFS and additional tumor types have been described in LFS families.3,4 Nevertheless, to our knowledge, the occurrence of thyroid carcinoma in LFS carriers has not been evaluated in the literature. A trial with fluorodeoxyglucose–positron emission tomography/computed tomography scans for cancer screening in LFS carriers identified 2 cases of papillary thyroid carcinoma in 15 asymptomatic carriers.5 Recently, a case report of a Spanish patient with papillary thyroid carcinoma at age 36 years was published.6
Regarding sporadic thyroid cancer, based on the Surveillance, Epidemiology, and End Results database, approximately 1.1% of men and women will receive a diagnosis of thyroid cancer at some point during their lifetime, with a median age at diagnosis of 51 years.7 In Brazil, the incidence of sporadic thyroid cancer for men and women is 1.2 and 5.3 cases per 100 000 per year, respectively.8 Although the majority of thyroid cancers are sporadic, some hereditary syndromes are associated with high risk for thyroid cancer, such as adenomatous polyposis, Cowden syndrome, and tuberous sclerosis, but not LFS.9
The incidence of LFS has been estimated as 1 in 5000 live births worldwide. Studies from the south and southeast of Brazil indicate that the incidence of LFS in these regions is much higher, and mainly due to a founder germline TP53 mutation in the oligomerization domain (exon 10) (c.1010G>A, p. Arg337His), which occurs in approximately 1 in 300 newborns (0.3%).10 The tumor profile among Brazilian carriers is similar to classic DNA-binding domain mutations found elsewhere in the world, but some age difference and a higher risk for other types of tumors may exist. Because thyroid cancer is not part of the core LFS tumor spectrum, the aim of this study was to determine the pattern of its occurrence in this specific population.
A retrospective study of Brazilian LFS carriers observed in the Department of Oncogenetics at A.C. Camargo Cancer Center, São Paulo, Brazil, was approved by the ethics committee in 2014. A waiver of informed consent of study participants was granted by the ethics committee due to the retrospective nature of the study. Data about the tumor spectrum developed by the carriers were obtained from medical records from 2001 to 2015.
A total of 193 TP53 p.R337H mutation carriers were identified. In this analysis, breast cancer and soft-tissue sarcoma were also the most prevalent tumors in adults, and, interestingly, thyroid cancer was observed in unusual prevalence.
Among 193 TP53 p.R337H mutation–positive patients from 58 families, 101 were cancer affected and 11 of these had the diagnosis of thyroid carcinoma (10.9%): 3 men and 8 women. The overall mean age at diagnosis was 44 years (median [SD], 43 [14.77] years). Five of 58 families (9%) had at least 1 family member with thyroid carcinoma: we observed 5 cases in 1 family, 3 cases in another family, and 3 more families with 1 case each. All the cases were histologically classified as papillary carcinomas, with 2 of them exhibiting follicular variant (Table and eFigures 1-4 in the Supplement).
In the literature, in a review of a French cohort of 415 LFS carriers with classic DNA-binding domain mutations in the TP53 gene, thyroid carcinoma was present in only 0.9% of the patients.2
Our results encourage further studies to elucidate whether thyroid cancer is related to LFS, as it is the fifth most prevalent tumor in women. Its incidence is a sporadic event in families with this cancer predisposition syndrome. Defining this issue would contribute to improving clinical and genetic management of these patients with thyroid cancer.
Of 101 p.R337H TP53 mutation–carrying family members with cancer in our study, 11 had thyroid cancer (10.9%). Although it is an uncommon manifestation of LFS in general, our findings revealed that thyroid carcinoma appears to be a component of the spectrum of tumors in carriers with the founder TP53 p.R337H mutation.
Our results show that thyroid carcinoma may be a component of LFS. Therefore, these findings strengthen the importance of early and regular thyroid imaging screening in individuals with the founder TP53 p.R337H mutation in Brazilian carriers, particularly among those with a family history of thyroid cancer.
Accepted for Publication: November 17, 2016.
Corresponding Author: Maria Nirvana da Cruz Formiga, MD, Department of Oncogenetics, A.C. Camargo Cancer Center, 211, Professor Antonio Prudente Street–Liberdade, 01509-900 São Paulo, SP Brazil (email@example.com).
Published Online: January 19, 2017. doi:10.1001/jamaoncol.2016.6389
Author Contributions: Drs Formiga and Achatzhad full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Formiga, Achatz, Kowalski.
Acquisition, analysis, or interpretation of data: Formiga, Achatz, de Andrade.
Drafting of the manuscript: Formiga, Achatz, de Andrade.
Critical revision of the manuscript for important intellectual content: Formiga, Kowalski, de Andrade.
Statistical analysis: Formiga, de Andrade.
Supervision: Achatz, Kowalski.
Conflict of Interest Disclosures: None reported.