Clinical genome sequencing in patients with hereditary breast and ovarian cancer: Concept, implementation and benefits

Abstract

Hereditary breast and ovarian cancer (HBOC) is one of the most frequent genetic cancer predisposition syndromes. Individuals at risk are identified mainly by family history and histopathological criteria. The current standard genetic testing is exome or panel sequencing. However, many high-risk families remain genetically unexplained. Genome sequencing has the potential to increase the diagnostic yield. This single-center real-world study aims to evaluate advantages of short-read genome sequencing (GS) in HBOC families. We report genome sequencing results of 818 index patients, who fulfilled clinical criteria for genetic testing. Data analysis showed less sequencing gaps and a more uniform coverage compared to a large cohort of in-house exomes. Samples were sequenced at an average depth of 41.2x for the HBOC core genes. Pathogenic variants were found in 9 of 13 core genes in 12.2 % of the patients. GS allowed the classification of a BRCA1 duplication and detected a whole-exon inversion in BARD1, as well as a deep intronic CHEK2 variant. Furthermore, we successfully used the BRIDGES-PRS in our HBOC cohort and found a significant effect size compared to the control cohort (p = 4.804^-14, Cohen's-D: 0.476), proving the transferability to a German cohort. GS offers a wealth of information, including the improved detection of structural variants, copy number variants, and parallel detection of complex genetic markers. This has the potential for future analyses, including intronic and intergenic regions. Finally, it also allows for a more streamlined process by converging several tests into one. The approach presented will give guidance for the implementation of GS in HBOC diagnostics.

Keywords: Clinical genome sequencing; HBOC; Hereditary breast and ovarian cancer; Next-generation sequencing; PRS; Polygenic risk scores; Short read sequencing.

Fig. 1

Study flow chart: HBOC diagnostic concept. Blue: routine diagnostics, which were performed for every patient; orange: case based verification of insertion site of duplicated regions of unsolved, structural variants; green: case based extended research; pink: optional screening for (likely) pathogenic variants in actionable genes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Structural variants of interest (visual illustration): Structural variants detected by short-read GS and long-read GS. Panel A shows a tandem duplication of exon 12 of BRCA1 identified by short-read GS. The detection of a tandem duplication is possible through the interpretation of split reads from which information regarding the localization of the breakpoints can be obtained. Panel B presents a tandem duplication of exons 62 and 63 of the ATM gene, identified by long-read GS. Short-read GS did not span the flanking repeats and therefore the exact breakpoint position could not be detected. Question marks in panel B indicate the potential location of the break point and uncertainty on a base pair resolution due to the repetitive structure.