Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study

Abstract

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%–26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6–34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

Plain language summary

The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes BRCA1 and BRCA2 and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had BRCA1/2 mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. BRCA1/2 mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the BRCA1/2 genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types.

TWEETABLE ABSTRACT

Among 9457 patients across 15 solid tumor types, we found that 4.7% had BRCA1/2 mutations, 13.6% had mutations in homologous recombination repair genes and 20.6% had gLOH ≥16%. The prevalence of mutations varied by tumor type.

Summary points

• The prevalence of mutations in homologous recombination repair (HRR) genes and of genomic loss of heterozygosity (gLOH) and the allelic and hereditary status of these mutations across solid tumor types are not well described.

• This study reports the prevalence of mutations in BRCA1/2 and in 13 other HRR genes and of gLOH across 15 tumor types, including tumor types beyond those more commonly associated with these biomarkers.

• Almost 5% of tumor samples had BRCA1/2 mutations, 14% had mutations in any of the HRR genes and 21% had a high prevalence of gLOH (gLOH ≥16%).

• The highest prevalences of were BRCA1/2 mutations in ovarian (13.1%), prostate (9.3%), breast (8.2%) and pancreatic (4.9%) cancers.

• The prevalence of BRCA1/2 mutations in mesothelioma, bladder cancer, endometrial cancer and gastric cancer were not negligible.

• Among tumors where biallelic status was determined, the biallelic proportions of BRCA1/2 mutations were 95% in prostate, 86% in ovarian, 83% in breast, 77% in pancreatic cancer and from 23% (gastric cancer) to 38% (bladder cancer) in other tumor types.

• Among tumors where heritable status was determined, germline BRCA1/2 mutations predominated in pancreatic and breast cancers, whereas somatic mutations were the majority in ovarian and most of the other tumor types.

• Across all tumor types, the proportion of gLOH ≥16% was highest in those with biallelic mutations of BRCA1, BRCA2 and PALB2.

• The prevalence of mutations in HRR genes varied considerably across tumor types.

• Evaluation of HRR gene alterations and gLOH may enable identification of tumors that are susceptible to drugs that act by causing double-strand DNA breaks.

Keywords: :

• BRCA1
• BRCA2
• homologous recombination
• loss of heterozygosity
• mutation
• neoplasms

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2367957

Author contributions

C Shao, E J Dettmana, A Gozmana, F Jina and W Zhoua conceptualized the study. C Chena, C Shao, E J Dettmana, Y Rena, H Zhoua, L C Leea performed formal analysis, visualization and validation. C Chena, C Shao, E J Dettmana, Y Rena, H Zhoua, L C Leea and W Zhoua performed project administration. C Shao, C Chena, E J Dettmana, Y Rena, H Zhoua, L C Leea, R Cristescua, A Gozmana, F Jina and W Zhoua performed the methodology. C Shao, R Cristescua and W Zhoua supervised. C Shao, C Chena, E J Dettmana, Y Rena, H Zhoua, L C Leea, R Cristescua, A Gozmana, F Jina and W Zhoua did the writing – original draft. C Shao, C Chena, E J Dettmana, Y Rena, H Zhoua, L C Leea, R Cristescua, A Gozmana, F Jina and W Zhoua did the writing – review and editing. All authors approve the final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial disclosure

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and shareholders in Merck & Co., Inc., Rahway, NJ, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

Medical writing was provided by ScribCo. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Additional study assistance was provided by Matthew J Marton, PhD and Ping Qiu, PhD of Merck & Co., Inc., Rahway, NJ, USA.

Ethical conduct of research

The Institutional Review Board approval for the Flatiron Health Clinico-Genomic data set (FH-FMI CGDB) was obtained by Flatiron Health prior to the present study. The Institutional Review Board of WCG Clinical (Princeton, NJ) gave ethical approval for the study protocol based and included a waiver of informed consent (approval ID 420180044).

Data availability statement

The US Flatiron Health-Foundation Medicine clinic-genomic database (FH-FMI CGDB) data that support the findings of this study were commercially licensed from the data vendor and are therefore not available. However, all relevant data are within the manuscript and its Supplemental Materials.

Additional information

Funding

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and shareholders in Merck & Co., Inc., Rahway, NJ, USA.