Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service

Abstract

Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources.

Figure 1

Study design and main results. This flowchart depicts the criteria for patient inclusion/exclusion of patients, the distribution of samples across the different massive parallel sequencing methodologies, as well as the results of pathogenic and likely pathogenic variants (PV/LPV) detected in this study. ¹Results not provided. ²Private laboratories: eight patients were sequenced using gene panels that included BRCA1/2 and TP53 (panels with 16 to 207 genes); and eight patients were sequenced only for BRCA1/2 genes, while TP53 was later sequenced through Sanger sequencing at our laboratory, except for one patient for which DNA sample was not available. In total, 227 patients were sequenced only for BRCA1/2 and TP53 genes (219 in-house and eight at private laboratories), while only 30 patients were sequenced for genes beyond BRCA1/2 and TP53.

Figure 2

Clinicopathological characteristics and familial history of all carriers of PV, LPV or VUS in BRCA1, BRCA2 or TP53 genes. Each column represents the data of a single carrier, and columns are sorted by variant classification (PV/LPV × VUS), gene, HBOC first tumor, laterality, receptor status, relatives with cancer, and relatives with HBOC cancer. All carriers presented BC, OC or pancreatic cancer as first tumors; except the carrier of BRCA1 VUS c.5348T > C, p.Met1783Thr, which presented thyroid cancer as first malignancy and BC as second. Carrier of p.Gln563Ter PV in BRCA1 (11th column) also carries a non-coding VUS in BRCA1 (c.441 + 8C > T). Gene panel size indicates if only BRCA1, BRCA2 and TP53 (= 3) were sequenced, or if the gene panel included other genes (totaling 16, 25 or 39 genes); but only 30 patients in the cohort were sequenced for genes beyond BRCA1/2 and TP53 (see Fig. 1). Carrier of p.Ile943Val VUS in BRCA2 (55th column) is the only patient with PV/LPV or VUS in BRCA1, BRCA2 and TP53 genes that also carries a PV/LPV in another gene (ATM PV c.640del, p.Ser214fs). See colored legend for details on each clinicopathological category. IDC: invasive ductal carcinoma. ILC: invasive lobular carcinoma. Localized: stages 0, I or IIA. Regional: stages IIB or III. Distant: stage IV.

Figure 3

Predictive power of detecting PV/LPV carriers (performance) in (A) BRCA1 only, (B) BRCA2 only, (C) BRCA1 and BRCA2, or (D) BRCA1, BRCA2 and TP53, in two subgroups: FH(−) = patients with no familial history of cancer (n = 90); FH(+) = patients with familial history of cancer (n = 167). Performance was estimated through Receiver Operating Characteristic (ROC) curves for BOADICEA and Penn II risk prediction models, as well as for the familial history data (number of relatives with cancer). FH(−) positive or FH(+) positive refer to the percentage of PV/LPV cases in each subgroup. Relatives w/cancer refers to the number of relatives with cancer. Relatives w/HBOC refers to the number of relatives with HBOC core cancer, which was defined, for convenience, as breast, ovarian, pancreatic, and prostate cancer. The corresponding area under the ROC curve (AUC) and p-value are presented, as well as the optimal cutoff point (marked by a dot) estimated through the Youden index.