Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jan 3;22(1):13.
doi: 10.1186/s12885-021-09082-y.

Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets

Zhongwu Lai  1 , Matthew Brosnan  2 , Ethan S Sokol  2 , Mingchao Xie  3 , Jonathan R Dry  3   4 , Elizabeth A Harrington  5 , J Carl Barrett  3 , Darren Hodgson  3
Affiliations

Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets

Zhongwu Lai et al. BMC Cancer. .

Abstract

Background: DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types.

Methods: Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB).

Results: Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types.

Conclusions: Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

Keywords: Breast; Genomic loss of heterozygosity; Germline; Homologous recombination deficiency; Homologous recombination repair; Immune checkpoint inhibitors; Loss of function; Ovarian; PARP inhibitors; Somatic; cancer.

PubMed Disclaimer

Conflict of interest statement

ZL, MX, EAH, JCB and DH are employees of, and hold stock in AstraZeneca. MB and ES are employees of Foundation Medicine Inc., Cambridge, MA, USA. JD declares no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan-Meier estimates of a progression-free survival and b overall survival by BRCA status in the TCGA ovarian cancer cohort
Fig. 2
Fig. 2
HRD-LOH scores by BRCA mutation in Foundation Medicine ovarian and breast cancer cohorts a germline versus somatic versus wild-type, b heterozygous (mono-allelic loss without LOH) versus homozygous (bi-allelic loss of function with LOH) versus compound heterozygous (bi-allelic loss of function without LOH) (observed in breast cancer cohort only) versus wild-type. Comphet, compound heterozygous; Het, heterozygous; Hom, homozygous
Fig. 3
Fig. 3
a HRR gene mutation prevalence in the Foundation Medicine dataset across six tumour types and b bi-allelic loss of function rates of HRR gene mutations in the Foundation Medicine dataset across six tumour types. To prevent multiple counting of a patient so that they are not over-estimated in samples that have a mutation in multiple genes only, one was chosen for representation based upon biological significance, for example, when BRCA is present, it will be called BRCA, even though an ATM is also detected
Fig. 4
Fig. 4
Likely BRCA1 and BRCA2 reversion mutations found in the cohort. For each gene, the boxes in the middle indicate protein and domain structures. Numbers below indicate amino acid numbering for the protein. Above the protein structure are the sensitizing mutations and below are candidate reversion mutations. Triangle indicates that the mutation is an indel resulting in frameshift, circle indicates SNV, and rectangle indicates in-frame deletion. Each colour represents a unique sample. The bar below indicates the location of exon 11, the largest exon for BRCA1 and BRCA2
See this image and copyright information in PMC

References

    1. O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547–560. - PubMed
    1. Schweizer MT, Antonarakis ES. Prognostic and therapeutic implications of DNA repair gene mutations in advanced prostate cancer. Clin Adv Hematol Oncol. 2017;15(10):785–795. - PubMed
    1. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–917. - PubMed
    1. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–921. - PubMed
    1. Dougherty BA, Lai Z, Hodgson DR, Orr MCM, Hawryluk M, Sun J, Yelensky R, Spencer SK, Robertson JD, Ho TW, et al. Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting. Oncotarget. 2017;8(27):43653–43661. - PMC - PubMed