Early-onset breast cancer patients in the South and Southeast of Brazil should be tested for the TP53 p.R337H mutation

Abstract

Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS), a disease that predisposes carriers to a wide variety of early onset tumors. In southern and southeastern Brazil, a high frequency of a germline TP53 mutation, p.R337H, was diagnosed in 0,3% of the population due to a founder effect. Carriers are at risk for developing cancer but the penetrance is lower than in typical DNA binding domain mutations. To date, only a few families were detected and diagnosis of carriers remains a challenge. Therefore, the inclusion of additional criteria to detect p.R337H carriers is necessary for the Brazilian population. We assessed the A.C. Camargo Cancer Center Oncogenetics Department database in search of common characteristics associated with p.R337H families that did not fulfill LFS/LFL clinical criteria. Among 42 p.R337H families, three did not meet any LFS/LFL criteria. All cases were young female patients with breast cancer diagnosed before age 45 and with no family history of LFS linked-cancers. Our results suggest that screening for the germline TP53 p.R337H mutation should be indicated, along with BRCA1 and BRCA2 genetic testing, for this group of patients, especially in the South and Southeast of Brazil.

Clinical implications of germline mutations in breast cancer: TP53

“…Individuals with this mutation have a similar lifetime cancer prevalence to other LFS carriers (about 90%) but a lower penetrance at young ages (< 20% at age 30 years, compared to 50% in other LFS carriers) [ 19 ]. It has been suggested that women affected with breast cancer under the age of 45 years in Southeast and Southern Brazil should be offered testing for this mutation, irrespective of family history [ 20 ]. The R337H mutation is not common among women diagnosed with breast cancer in Portugal [ 21 ].…”

Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations

“…The most notable property of p53 is its action as a transcription factor [83]. We found three articles that studied variations in TP53, all in Brazilian populations [31,84,85]. These articles studied the c.1010G>A (p.R337H) mutation, which occurs at a high frequency in southern and southeastern Brazil [86][87][88][89][90].…”

“…Giacomazzi et al [84] reported that the prevalence of p.R337H was higher in women diagnosed with BC at or before 45 years of age (12.1%) than in those diagnosed at 55 or older (5.1%). An article by Andrade et al [85] suggested that screening for the germline TP53 p.R337H mutation should be recommended for young females with no family history of cancers associated with Li-Fraumeni syndrome. The three authors agree that inheritance of the c.1010G>A variant may significantly contribute to the high incidence of BC in Brazil.…”

Li‐Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition

“…The fact that none of the carrier parents in this study had cancer at the time of writing of this report suggested that the TP53 R337H mutation was associated with a lower penetrance compared to other germline TP53 mutations. Although initial reports suggested that the main cancer risk associated with the TP53 R337H mutation was the development of childhood ACC, more recent studies reveal that this mutation can be also be identified in patients with CPC, OS, breast cancer and, more recently, neuroblastoma (Giacomazzi et al , ; Seidinger et al , ; Andrade et al , ). All told, it is likely that TP53 R337H predisposes to the more typical cancers seen in LFS, albeit with a lower penetrance.…”