Differences in somatic TP53 mutation type in breast tumors by race and receptor status

Abstract

Purpose: Somatic driver mutations in TP53 are associated with triple-negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status.

Methods: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher's exact test.

Results: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p = 0.04). Mutations with DNE activity were positively associated with TNBC (OR 1.37, p = 0.03) and estrogen receptor (ER) negative status (OR 1.38; p = 0.005).

Conclusions: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER-negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings.

Keywords: Breast cancer; Dominant negative; Gain-of-function; Loss-of-function; Racial differences; TP53.

Figure 1:. TP53 Gene Structure and Mutation Frequency

(a). A diagram of the intron/exon structure of TP53 is drawn to scale. A green arrow denotes the exon containing the start codon and a red arrow denotes the exon containing the stop codon.(b). The frequency of somatic TP53 mutations by codon is plotted. Exons 5 through 8 are denoted by a red line. Intronic mutations affecting splicing are not included. The figure was created in GraphPad Prism 8.

Figure 2:. Association of age of breast cancer diagnosis with TP53 mutation characteristics

The frequency of age of breast cancer diagnosis of all individuals included in the study was plotted by histogram (a). Age of diagnosis was not significantly associated with TP53 GOF versus LOF, p-value =0.5 (b) or dominant negative effect, p-value 0.49 (c). Individuals with a TP53 mutation at a CpG hotspot were slightly, but not significantly younger at age of diagnosis (53.6 years versus 55.0 years), p-value 0.065 (d). P-values were calculated using a Welch two sample T-test. P-values < 0.05 were considered significant. The figure was created in R.