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

Paskulin, Diego D’Ávila; Giacomazzi, Juliana; Achatz, Maria Isabel; Costa, Sandra; Reis, Rui Manuel; Hainaut, Pierre; Santos, Sidney Emanuel Batista dos; Ashton‐Prolla, Patrícia

doi:10.1371/journal.pone.0143262

Cited by 13 publications

(11 citation statements)

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“…The mutation TP53, c.1010G > A, has been previously reported as founder mutation in Southern Brazilian [ 30 ]. Interestingly, it was detected in one of the Chinese families who had breast and lung cancer and multiple family cancers.…”

Section: Discussionmentioning

confidence: 99%

Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients

Kwong

Shin

et al. 2020

BMC Cancer

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Background Germline TP53 mutations are associated with Li-Fraumeni syndrome, a severe and rare hereditary cancer syndrome. Despite the rarity of germline TP53 mutations, the clinical implication for mutation carriers and their families is significant. The risk management of TP53 germline mutation carriers is more stringent than BRCA carriers, and radiotherapy should be avoided when possible. Methods TP53 gene mutation screening was performed in 2538 Chinese breast cancer patients who tested negative for BRCA mutations. Results Twenty TP53 mutations were identified with high next-generation sequencing concerning for germline mutations in Chinese breast cancer families. The majorities of the TP53 carriers had early-onset, hormone receptor-positive breast cancer, and had strong family history of cancer. Among all, 11 patients carried a germline mutation and 6 of which were likely de novo germline mutations. In addition, 1 case was suspected to be induced by chemotherapy or radiation, as this patient had no significant family history of cancer and aberrant clonal expansion can commonly include TP53 mutations. Furthermore, we have identified one mosaic LFS case. Two novel mutations (c.524_547dup and c.529_546del) were identified in patients with early-onset. Conclusions In view of the high lifetime risk of malignancy, identification of patients with germline TP53 mutations are important for clinicians to aid in accurate risk assessment and offer surveillance for patients and their families.

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Section: Discussionmentioning

confidence: 99%

Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients

Kwong

Shin

et al. 2020

BMC Cancer

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“…The compound variant haplotype was enriched in patients with cancer, conferring risk for sarcoma and subsequent cancers. 16,17 The IARC germline TP53 data set contains data on 282 Brazilian carriers of the p.R337H variant (8.4%). Of these carriers, 193 (68.4%) met LFS testing criteria, including 141 participants (50.0%) who met these criteria on the sole basis of diagnosis of adrenocortical carcinoma in the family.…”

Section: Meaningmentioning

confidence: 99%

Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set

et al. 2021

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IMPORTANCE Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers that is caused by pathogenic TP53 germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking, and mechanisms leading to phenotypic differences remain largely unknown.OBJECTIVE To define the phenotypic spectrum of Li-Fraumeni syndrome and conduct phenotype-genotype associations across the phenotypic spectrum. DESIGN, SETTING, AND PARTICIPANTSWe analyzed and classified the germline variant data set of the International Agency for Research on Cancer TP53 database that contains data on a cohort of 3034 persons from 1282 families reported in the scientific literature since 1990. We defined the term Li-Fraumeni spectrum to encompass (1) phenotypic Li-Fraumeni syndrome, defined by the absence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting clinical Li-Fraumeni syndrome criteria; (2) Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in persons/families meeting Li-Fraumeni syndrome testing criteria; (3) attenuated Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family with cancer who does not meet Li-Fraumeni syndrome testing criteria; and (4) incidental Li-Fraumeni syndrome, defined by the presence of a pathogenic/likely pathogenic TP53 variant in a person/family without a history of cancer. Data analysis occurred from November 2020 to March 2021. MAIN OUTCOMES AND MEASURESDifferences in variant distribution and cancer characteristics in patients with a germline TP53 variant who met vs did not meet Li-Fraumeni syndrome testing criteria. RESULTSTumor spectra showed significant differences, with more early adrenal (n = 166, 6.5% vs n = 0), brain (n = 360, 14.17% vs n = 57, 7.46%), connective tissue (n = 303, 11.92% vs n = 56, 7.33%), and bone tumors (n = 279, 10.98% vs n = 3, 0.39%) in patients who met Li-Fraumeni syndrome genetic testing criteria (n = 2139). Carriers who did not meet Li-Fraumeni syndrome genetic testing criteria (n = 678) had more breast (n = 292, 38.22% vs n = 700, 27.55%) and other cancers, 45% of them occurring after age 45 years. Hotspot variants were present in both groups. Several variants were exclusively found in patients with Li-Fraumeni syndrome, while others where exclusively found in patients with attenuated Li-Fraumeni syndrome. In patients who met Li-Fraumeni syndrome genetic testing criteria, most TP53 variants were classified as pathogenic/likely pathogenic (1757 of 2139, 82.2%), whereas 40.4% (404 of 678) of TP53 variants identified in patients who did not meet the Li-Fraumeni syndrome genetic testing criteria were classified as variants of uncertain significance, conflicting results, likely benign, benign, or unknown. CONCLUSIONS AND RELEVANCEThe findings of this cohort study suggest that this new classification, Li-Fraumeni spectrum, is a step toward ...

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“…TP53 R337H is a founder mutation [10], and its increasing frequency in the population is facilitated by its low penetrance, with a relatively low cancer risk during the reproductive years. However, it is not clear how this mutation accumulated only in Southern Brazil from a Caucasian/Portuguese–Iberian common ancestor [11]. While R337H occurs in 1:370 births in Paraná state [3], other TP53 germline mutations are thought to occur at a frequency of between 1:5000 and 1:20,000 births [7,12] in other countries.…”

Section: Introductionmentioning

confidence: 99%

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil

Costa¹,

Gerber²,

Ibañez³

et al. 2019

Cancers

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The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

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

Cited by 13 publications

References 41 publications

Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients

Mutation screening of germline TP53 mutations in high-risk Chinese breast cancer patients

Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil

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