Prevalence of the TP53 p.R337H Mutation in Breast Cancer Patients in Brazil

Abstract

Germline TP53 mutations predispose individuals to multiple cancers and are associated with Li-Fraumeni/Li-Fraumeni-Like Syndromes (LFS/LFL). The founder mutation TP53 p.R337H is detected in 0.3% of the general population in southern Brazil. This mutation is associated with an increased risk of childhood adrenal cortical carcinoma (ACC) but is also common in Brazilian LFS/LFL families. Breast Cancer (BC) is one of the most common cancers diagnosed in TP53 mutation carriers. We have assessed the prevalence of p.R337H in two groups: (1) 59 BC affected women with a familial history (FH) suggestive of hereditary cancer syndrome but no LFS/LFL features; (2) 815 BC affected women unselected for cancer FH, diagnosed with BC at or before age 45 or at age 55 or older. Among group 1 and group 2 patients, 2/59 (3.4%, CI95%: 0.4%–11.7%) and 70/815 (8.6%, CI95%: 6.8%–10.7%), respectively, were p.R337H carriers in the germline. The prevalence of p.R337H was higher in women diagnosed with BC at or before age 45 (12.1%, CI95%: 9.1%–15.8%) than at age 55 or older (5.1%, CI95%: 3.2%–7.7%), p<0.001). The Brazilian founder p.R337H haplotype was detected in all carriers analysed. These results suggest that inheritance of p.R337H may significantly contribute to the high incidence of BC in Brazil, in addition to its recently demonstrated impact on the risk of childhood ACC.

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

“…Silva et al [31] reported a frequency of 2.5% for this variant and suggested that all BRCA-negative female BC patients with clinical criteria for hereditary breast-ovarian cancer should be tested for the c.1010G>A variant. 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 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].…”

Genomic Disparities in Breast Cancer among Latinas

“…90 This mutation occurs in 2.4% to 8.6% of Brazilian women with breast cancer. 72,73,90,91 In a large study, which included 403 patients with breast cancer diagnosed at 45 years or younger, 12.1% carried the TP53 R337H mutation. Although the mutation was significantly more frequent in younger patients compared with those diagnosed at or above age 55 years ( P < .001), 5.1% of the older group carried the mutation.…”

“…Although the mutation was significantly more frequent in younger patients compared with those diagnosed at or above age 55 years ( P < .001), 5.1% of the older group carried the mutation. 73 To date, no other populations have been identified in whom TP53 makes such a significant contribution to breast cancer. The prevalence of this mutation in southern Brazil has been estimated be approximately 0.3%.…”

Recent developments in brain tumor predisposing syndromes

“…Carriers of this specific TP53 mutation (R337H) have a low risk of developing cancer before the age of 30, but a lifetime cancer risk comparable to classic LFS [105,106]. Interestingly, 90-95% of all patients with adrenocortical carcinomas have the TP53-R337H mutation leading to a drastic increase of this cancer form in the southern provinces of Brazil [107].…”