High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands

Abstract

Background: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands.

Methods: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome.

Results: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs.

Conclusion: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.

Keywords: Blood relative analysis; Cascade testing; Genetic testing; Hereditary breast and ovarian cancer syndrome; Pathogenic germline variant.

Fig. 1

Study design. We first sequenced the exomes of 1,023 BRCA1/BRCA2 wild-type Japanese patients with familial breast cancer (probands). Samples from 684 family members (682 BRs and 2 spouses) of 281 probands, selected from availability of samples, were subsequently rendered to exome or target-panel sequencing. We analyzed prevalence and risk class of mutated genes of the probands and BRs focusing on 30 HBOC-causative genes. BR, blood relative; PGV, pathogenic germline variant; ACMG, the American College of Medical Genetics and Genomics; AMP, the Association of Molecular Pathology; and HBOC, hereditary breast and ovarian cancer

Fig. 2

Differences in mutated genes between probands and BRs. A Frequency of PGV carriers among probands and BRs. Numbers of PGVs are shown. B Prevalence of risk class of mutated genes between probands and BRs. Shown are the number of PGVs per gene for probands and BRs (left panel) and the frequency of risk class for probands and BRs (right panel). Frequency is based on the number of cases. Note that all 281 probands had wild-type BRCA1/2 alleles due to the study design. The p value was computed using Fisher’s exact test for PGV carriers of high-risk genes. BR, blood relatives; PGV, pathogenic germline variant; OR, odds ratio; and 95% CI; 95% confidence interval

Fig. 3

Risk class of mutated genes and concordance of PGV detection in BRs. A Concordance of PGVs between probands and BRs. The number in the square indicates the specific BR with concordant or discordant detection of PGVs. Concordance is defined by the same PGV detection between the proband and BR; discordance is defined based on either the detection of a different PGV between the proband and BR, or detection of a PGV in the BR but not in the proband. B PGVs in the BRs of probands with or without PGVs. Frequency of cases is indicated. The p value was computed by Fisher exact test. C Frequency of risk class of mutated genes detected in the BRs of probands with or without PGV. Frequency is based on the number of cases. The p value was computed using Fisher’s exact tests. D Frequency of risk class of mutated genes in BRs of concordant (conc.) or discordant (disc.) PGV detection with respect to the proband. Frequency is based on the number of PGVs. BR, blood relative; PGV, pathogenic germline variant; OR, odds ratio; and 95%CI, 95% confidence interval

Fig. 4

Prevalence, risk class, and concordance of PGVs in BRs with (affected) or without (unaffected) cancer history. A Prevalence of PGVs in BRs with (affected) or without (unaffected) cancer history. Frequency is based on the number of cases. B Frequency of risk class of mutated genes in BRs with (affected) or without (unaffected) cancer history. Frequency is based on the number of cases. C Concordance of PGV detection in BRs with (affected) or without (unaffected) cancer history. Frequency is based on the number of PGVs. BR, blood relative; PGV, pathogenic germline variant