The breast cancer immunophenotype of TP53-p.R337H carriers is different from that observed among other pathogenic TP53 mutation carriers

Abstract

Germline TP53 mutations are associated with Li-Fraumeni syndrome, an autosomal dominant disorder characterized by a predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are clustered within the DNA-binding domain of the gene, disrupting the structure and function of the protein. A specific germline mutation in the tetramerization domain of p53, p.R337H, was reported at a high frequency in Southern and Southeastern Brazil. This mutation appears to result in a more subtle defect in the protein, which becomes functionally deficient only under particular conditions. Recent studies show that the BC phenotype in TP53 mutation carriers is often HER2 positive (63-83%). Considering that the immunophenotype of BC among p.R337H carriers has not been reported, we reviewed immunohistochemistry data of 66 p.R337H carriers in comparison with 12 patients with other non-functional TP53 germline mutation. Although 75% of carriers of these mutations showed significant HER2 overexpression (3+), corroborating previous studies, only 22.7% of p.R337H patients had BC overexpressing HER2. These results reinforce the notion that different germline mutations in TP53 may predispose to BC via different mechanisms.

What 20 years of research has taught us about the TP53 p.R337H mutation

“…34 However, a Brazilian study of 78 patients with breast cancer demonstrated that the median age at breast cancer diagnosis in a group of p.R337H carriers (n = 66) was 42 years, which was older than the median age at diagnosis (30 years) for carriers of other nonfunctional germline TP53 mutations. 35 In addition, most patients had a positive hormone receptor status, and in contrast to other studies, HER2+ breast cancer was very similar to that observed in noncarriers of TP53 variants. 35 Numerous sarcoma types collectively constitute less than 1% of all cancers and often occur sporadically.…”

“…35 In addition, most patients had a positive hormone receptor status, and in contrast to other studies, HER2+ breast cancer was very similar to that observed in noncarriers of TP53 variants. 35 Numerous sarcoma types collectively constitute less than 1% of all cancers and often occur sporadically. However, sarcomas represent 17.4% of all cancers in TP53 germline mutation carriers and 36.8% of all cancers in patients younger than 20 years.…”

“…32,33 The age of onset is later in comparison with LFS-associated breast cancer. 35 It tends to be negative for HER2. 35 Phyllodes carcinoma has been reported.…”

“…35 It tends to be negative for HER2. 35 Phyllodes carcinoma has been reported. 20,40 Secondary primary malignancies, including contralateral cases, have been documented in 50% of cases and are enriched in carriers of the extended haplotype.…”

Current review ofTP53pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome

“…The detection rate may be especially increased in women with HER2+ breast tumors, although this is based only on one study. Interestingly, there is published evidence that patients with the reduced penetrance Brazilian founder pathogenic variant c.1010G>A (p.Arg337His) are less likely to develop HER2+ breast tumors than other TP53 carriers (Fitarelli‐Kiehl et al., ), inferring that HER2‐positive tumor status may be less predictive for p.Arg337His and potentially other reduced penetrance variants.…”