Next-generation sequencing based detection of BRCA1 and BRCA2 large genomic rearrangements in Chinese cancer patients

Abstract

BRCA1/2 mutation is a biomarker for guiding multiple solid tumor treatment. However, the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in Chinese cancer patients has not been well revealed partially due to technical difficulties in LGR detection. This study utilized next-generation sequencing (NGS) to analyze the BRCA1/2 mutation profile, including LGR, in 56126 Chinese cancer patients. We also reported that two ovarian and breast cancer patients with NGS-determined BRCA1/2 LGR benefited from PARP inhibitors (PARPi). DNA sequencing identified BRCA1/2 variants (including LGR, pathogenic and likely-pathogenic variants) in 2108 individuals. Seventy patients were discovered to harbor germline LGRs in BRCA1 and 14 had germline LGRs in BRCA2. Among the LGRs detected, exon 1-2 deletion was the predominant LGR (14/70) in BRCA1, and exon 22-24 deletion was the most frequent LGR (3/14) in BRCA2. Notably, the BRCA1 exon 7 deletion was a novel LGR and was identified in six patients, suggesting a specific LGR in Chinese cancer patients. The prevalence analysis of BRCA1 and BRCA2 LGRs across multiple cancers revealed that BRCA1 LGR more frequently occurred in ovarian cancer (1.31%, 33/2526), and BRCA2 LGR was more commonly seen in cholangiocarcinoma (0.47%, 2/425). Two ovarian and breast cancer patients with BRCA1/2 LGR benefited from PARPi therapy. This is the first study to reveal the BRCA1/2 LGR profile of a Chinese pan-cancer cohort by using an NGS-based assay. Two breast and ovarian cancer patients harboring NGS-determined BRCA1/2 LGR benefited from PARPi, indicating that NGS-based detection of BRCA1/2 LGR has the potential to guide PARPi treatment.

Keywords: BRCA; breast cancer; large genomic rearrangements; next-generation sequencing; ovarian cancer; pan-cancer.

Figure 1

The spectrum of large genetic rearrangements (LGRs) detected in BRCA1 and BRCA2 genes. Exon numbers are indicated on the top. The characteristics of the detected LGRs are listed on the left. The affected exons are shown as bars, among which, grey represents deletion, and orange indicates duplication. Actual locations of breakpoint are not implied.

Figure 2

Prevalence of BRCA1 (orange) and BRCA2 (blue) LGR across multiple cancer types. Cancer types included ovarian cancer (n = 2526), breast cancer (n = 1788), cholangiocarcinoma (n = 425), neuroendocrine (n = 152), prostate cancer (n = 1083), head and neck cancer (n = 801), endometrial cancer (n = 880), sarcoma (n = 1863), gastric cancer (n = 4427), kidney cancer (n = 1545), liver cancer (n = 4973), lung cancer (n = 23920) and colorectal cancer (n = 11743).

Figure 3

Imaging records of two patients who had BRCA1/2 LGRs and benefited from PARP inhibitors. (A) Magnetic resonance imaging (MRI) scan of the pelvic before and after fluzoparib treatment (ovarian cancer case). The red arrows indicate tumor lesions. (i) The pelvic MRI scan on March 5, 2021 revealed tumor status before fluzoparib treatment (5.5*3.4 cm). (ii) Pelvic MRI on June 9, 2021 indicated a significant decrease in tumor size (1.9 *1.6 cm) after fluzoparib treatment. (iii) The pelvic MRI scan on August 10, 2021 revealed progression of tumor lesions (3.0*4.2 cm) after 3 months of discontinuation of fluzoparib. (B) Computed tomography CT scan of the chest and magnetic resonance imaging (MRI) scan of the brain (breast cancer case). The red arrows indicate tumor lesions. (i) Chest CT in May 2017 revealed a metastatic lesion (approximately 2.3*1.8 cm) in the middle lobe of the right lung. (ii) The patient received surgery in September 2017 and maintenance therapy with olaparib. Chest CT in October 2021 indicated pulmonary metastasis disappeared during maintenance therapy with olaparib. (iii) Brain MRI in August 2017 revealed a metastatic lesion with ring-like enhancement in the left frontal lobe with peri-tumoral edema. (iv) Brain MRI in October 2021 indicated a significant shrinkage in brain metastasis lesions during the maintenance therapy with olaparib.