High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer

Our plain-English summary of High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer, by B. Bertelsen, I.V. Tuxen, C.W. Yde, et al (NPJ Genomic Medicine, 2019).

The study

• Authors: B. Bertelsen, I.V. Tuxen, C.W. Yde, M. Gabrielaite, M.H. Torp, S. Kinalis, O. Oestrup, K. Rohrberg, I. Spangaard, E. Santoni-Rugiu, K. Wadt, M. Mau-Sorensen, U. Lassen, F.C. Nielsen
• Journal: NPJ Genomic Medicine
• Published: 2019;4:13
• Cited by: 66 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.

In plain English

This study looked back at blood DNA from 636 patients with advanced solid cancers. They had been referred to a phase 1 cancer trial unit at Rigshospitalet in Copenhagen, Denmark, after their standard treatment options were exhausted. The authors searched 168 cancer-associated genes for inherited (germline) variants classed as pathogenic or likely pathogenic. Such variants were found in 17.8% of the patients (113 people). About half of the 121 variants (52%) were in genes for homologous recombination, a DNA-repair pathway that includes BRCA1, BRCA2 and the Fanconi anemia genes. Frequency differed by cancer type and was highest in malignant mesothelioma, at 7 of 12 patients (58%). Their variants were mostly in repair genes, among them BAP1, BRCA2 and several Fanconi anemia genes. Three of these mesothelioma patients had first-degree relatives with mesothelioma and a known history of asbestos exposure. The authors saw this as implying a gene-environment interaction. The article does not describe how asbestos exposure was assessed. The authors concluded that germline variants were frequent, especially in homologous recombination genes. They noted that patient numbers were limited for some cancer types, including mesothelioma, and that their sorting of variants by likely causality was only an assumption.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of germline whole exome sequencing in patients enrolled in a prospective personalized oncology study (CoPPO)
• Who was studied: 636 patients with advanced solid cancer and exhausted treatment options, referred to the Phase 1 unit at Rigshospitalet, Copenhagen, Denmark, and enrolled in the CoPPO study from May 2013 to February 2018. They included 12 patients with malignant mesothelioma; the article does not say whether these were pleural or peritoneal.
• Exposure: Inherited (germline) pathogenic or likely pathogenic variants in 168 cancer-associated genes, detected by whole exome sequencing of blood DNA. Asbestos exposure was not studied as an exposure; it is mentioned only for three mesothelioma patients and their families.
• Main results:
  • Of the 636 patients, 17.8% (n = 113) had a pathogenic or likely pathogenic germline variant in at least one of the 168 genes.
  • Malignant mesothelioma patients had the highest frequency of pathogenic germline variants: seven of twelve (58%).
  • The frequency of patients with variants ranged from 58% in malignant mesothelioma, 30% in ovarian cancer, 28% in cervical cancer, 25% in cancer of unknown primary origin and 25% in urothelial cancer, down to 5% in gastric cancer.
  • Across all cancer types, 52% of the pathogenic germline variants were in homologous recombination pathway genes.
  • In mesothelioma patients, more than half of the variants were in Fanconi anemia pathway genes (FANCA, FANCC, FANCD2, FANCM). Most mutated genes were in homologous recombination (BAP1, BRCA2, FANCA, FANCC, FANCD2, FANCM), plus one nucleotide excision repair gene (XPC).
  • Three mesothelioma patients carrying a pathogenic germline variant (in FANCD2, FANCM and XPC) had first-degree relatives with mesothelioma and a known history of asbestos exposure.
  • The authors interpreted these three mesothelioma cases as implying a gene-environment interaction.
  • Using a 65% tumor allele frequency cut-off, 19% of all identified pathogenic germline variants showed loss of heterozygosity in tumor samples. The figure was 27% for variants in homologous recombination genes.
  • A potential treatment target based on the germline variant was identified in 25 patients (4%): PARP inhibitors for 21 patients with a BRCA1/2 variant, and immunotherapy for 4 patients with a mismatch repair gene variant.
• The authors' conclusion: The authors concluded that patients with advanced solid cancers showed a high frequency of germline variants, especially in the homologous recombination pathway. They suggested that testing for selected germline variants in precision oncology may contribute to improved treatment.
• Limitations the authors state:
  • The number of included patients was limited for pancreatic cancer, mesothelioma and ovarian cancer, the cancer types where variants appeared concentrated in homologous recombination genes.
  • Loss of heterozygosity may have been underestimated because tumor biopsies contained varying amounts of normal tissue. The authors said these results should be interpreted with caution.
  • Sorting variants into likely or possible causes was only an assumption of causality.
  • Pedigrees and relatives' blood samples could not be obtained for each family.
  • Most patients had already received platinum-based chemotherapy, so the potential clinical benefit of PARP inhibitor treatment in these drug-resistant, advanced-stage patients remains unclear.

Topics

Medical terms in this study, explained in our Lexicon: Germline Mutation, Mesothelioma, Ovarian Cancer.

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• Assessing the function of homologous recombination DNA repair in malignant pleural effusion (MPE) samples — M.J. Patterson, R.E. Sutton, et al. (2014)
• The Association of BAP1 Loss-of-Function With the Defect in Homologous Recombination Repair and Sensitivity to PARP-Targeted Therapy — H. Yang, D. Xu, et al. (2020)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• A Prospective Phase II Single-arm Study of Niraparib Plus Dostarlimab in Patients With Advanced Non-small-cell Lung Cancer and/or Malignant Pleural Mesothelioma, Positive for PD-L1 Expression and Germline or Somatic Mutations in the DNA Repair Genes: Rationale and Study Design — F. Passiglia, P. Bironzo, et al. (2021)

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