Genomic instability in non-breast or ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2

Abstract

Background: Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features.

Methods: The full tumor history of a large, historical, clinic-based, consecutive cohort of 2965 individuals with germline pathogenic variants in BRCA1/2 was retrieved from the Dutch nationwide pathology databank (Palga). In total, 169 non-breast or ovarian malignancies were collected and analyzed using targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second-hit alterations and genomic instabilities indicative of homologous recombination deficiency, respectively.

Results: BRCA1/2 deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively).

Conclusions: BRCA1/2 deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. Evaluation of the effectiveness of poly(ADP-ribose) polymerase inhibitors in these individuals should be focused on tumors with a confirmed absence of a wild-type allele.

Figure 1.

Malignancies in individuals with a germline pathogenic variant in BRCA1 or BRCA2. A) Flowchart of the cohort and malignancy selection. B) Overview of individuals with or without malignancies, by gene and identification history. In the inner circle, the fraction of women and men is represented. Outer circles show that 1, 2, 3, 4, 5, 6, 7, or 8 developed malignancies in the fraction of individuals for breast carcinoma, ovarian carcinoma, prostate carcinoma, and other malignancies. A unique set of malignancies needed to occur in at least 2 individuals to be visualized. C) Standard incidence ratios for individuals with germline pathogenic variants in BRCA1 at 20-69 years of age. Cancer incidence in both the index individual and relatives with germline pathogenic variants in BRCA1 were included in the analysis and compared with the cancer incidence of the general Dutch population. No significantly increased incidence, significantly decreased incidence, or significantly increased incidence is shown by cancer type. Numbers are given by type of malignancy on the left of the figure. Malignancies with a potential selection bias because of breast or ovarian cancer surveillance measures are separated from other malignancies by a black line. Cancers that occurred in 5 or fewer individuals were grouped as “others.” D) Standard incidence ratios for individuals with germline pathogenic variants in BRCA2 at 20-69 years of age. Cancer incidence for both the index individual and relatives with germline pathogenic variants in BRCA2 were included in the analysis and compared with the cancer incidence of the general Dutch population. No significantly increased incidence or significantly increased incidence is shown by malignancy. Numbers are given by type of malignancy on the left of the figure. Malignancies with a potential selection bias because of breast or ovarian carcinoma surveillance measures are separated from other malignancies by a black line. Cancers that occurred in 5 or fewer individuals were grouped as “others.” ^aMetastases were removed for the standard incidence ratio analysis. Palga = Dutch nationwide pathology databank; N/A = not applicable.

Figure 2.

BRCA1/2 deficiency and genomic instability score, by tumor type, in individuals with a pathogenic germline variant in BRCA1 or BRCA2. A, B) The left images show the frequency of BRCA status, by cancer tissue, in individuals with germline pathogenic variants in BRCA1 (A) or BRCA2 (B). Deficiency is based on targeted sequence analyses and the shallow whole-genome sequencing–based copy number analyses of the respective genes. Data were analyzed for BRCA1/2 deficiency, BRCA1/2 proficiency, and inconclusive results. The number of tested malignancies is given, by malignancy type, at the left of the figure. A, B) The right images show the genomic instability score for each malignancy in individuals with germline pathogenic variants in BRCA1 (A) or BRCA2 (B), by tumor type. Genomic instability scores are calculated by the sum of large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. BRCA status results show malignancies with BRCA1/2 deficiency, BRCA1/2 proficiency, and inconclusive results. “Others” include malignancies of soft tissue sarcomas, stomach, small bowel, kidney, larynx, oral cavity, testis, thyroid, and uterus, included in Supplementary Figure 2 (available online). C) Box plot of the genomic instability score, by BRCA status and gene. BRCA status results show malignancies with BRCA1/2 deficiency, BRCA1/2 proficiency, and inconclusive results. ns = not significant. *P < .05, **P < .01, ***P < .001. D) Box plot of the genomic instability score, by genomic ploidy and BRCA status. Genomic ploidy is diploid, triploid, or tetraploid. BRCA status results show malignancies with BRCA1/2 deficiency, BRCA1/2 proficiency, and inconclusive results. ns = not significant; *P < .05, **P < .01, ***P < .001.

Figure 3.

Contribution of different types of genomic aberrations to the homologous recombination status of malignancies in individuals with germline pathogenic variants in BRCA1/2. A, B) The count of large-scale state transitions (rectangle), telomeric allelic imbalances (triangle), and genomic loss of heterozygosity (circle) for each malignancy in individuals with germline pathogenic variants in BRCA1 (A) or BRCA2 (B) were visualized and categorized by ovarian cancer controls, malignancies with BRCA1/2 deficiency, malignancies with BRCA1/2 proficiency, and malignancies with inconclusive somatic mutation results and sorted based on large-scale state transition scores. The result of the somatic mutation analysis and the tissue of origin for each malignancy is given below the figure. Somatic aberrations represent loss or inactivation of the wild-type allele, pathogenic somatic mutation, no second hit detected, loss of the mutant allele, or inconclusive results. Genomic ploidy represents diploid, triploid, or tetraploid genomic status. Malignancies analyzed were ovarian cancer controls; prostate, pancreatic, colorectal, lung, urinary tract, endometrial, and esophageal carcinomas; melanoma; lymphoma; and other malignancies (included in Supplementary Figure 2, available online).