Germline testing for homologous recombination repair genes—opportunities and challenges

Abstract

Pathogenic variants in the BRCA1 and BRCA2 genes are well known causes of hereditary breast and ovarian cancer. Other genes involved in the homologous recombination pathway can also be associated with increased probability of cancer development, for example, breast and ovarian cancer, prostate and pancreatic cancer, colorectal cancer, and even childhood tumors like medulloblastoma. Traditionally, patients and families likely to harbor a genetic predisposition have been identified using personal and family history. Several checklists and risk prediction tools have proven to be useful in the clinic. Through the widespread application of next generation sequencing of tumor tissue, a growing number of individuals with genetic cancer predisposition is now identified molecularly, even in the absence of a suggestive family history. Any constitutional variant identified during molecular genetic testing has to be assessed for its relevance, both functionally and in the context of patient phenotype. Variant curation is time consuming, but has been increasingly standardized by introduction of several guidelines to allow reliable and reproducible classification of constitutional variants. Variant classification by expert panels using data mining tools, evidence‐based decision trees and gene specific criteria represents the gold standard. Participation of geneticists in molecular tumor boards facilitates the curation of potential constitutional variants, germline validation and thus directing the patient to appropriate counselling and care pathways. Due to the high relevance of germline variants for treatment and surveillance of the index patient and predictive testing and surveillance of relatives, only pathogenic or likely pathogenic variants must be used for clinical decision‐making.

Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions

“…In terms of each risk factor, our results suggest that the frequencies of BRCA mutations in early-onset breast cancer, familial breast cancer, TNBC and bilateral breast cancer (19.4-38.5%) are higher than those observed in other Chinese population studies (2.3-12.5%) (Gavande et al, 2016;Li et al, 2019;Sherill-Rofe et al, 2019;Abida et al, 2020;Hirsch et al, 2020;Foo et al, 2021) and the frequencies of non-BRCA mutations are also at a high level (7.7-17.5%). However, no pathologic variants were observed in the male patients in our study.…”

H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models

“…A quicker acquisition of mutations or genomic rearrangements could result in tumor development, adaptation to changing conditions, development of resistance, or immune evasion. As an example of these scenarios, it is well established that germline mutations affecting DNA repair genes increase the rate of tumor incidence, thus, these mutations can be considered tumor drivers while at the same time conferring vulnerabilities to the cells (i.e., genomic instability, replication stress, reduced proliferation due to cell cycle checkpoint activation, increased susceptibility to DDR inhibitors) ( 53 ). Along this line, we showed that human G34-mutant pHGGs had increased genomic CNAs compared with H3.3-WT pHGGs.…”

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

“…This approach would drastically decrease the workload for the molecular pathologist, shorten the time to clinical report, and greatly simplify the interpretation of results for the receiving provider or patient, which are time-intensive and potentially prohibitive. 27 , 28 It is important to acknowledge that many barriers exist to performing paired tumor-normal analysis including challenges in collecting tumor and blood samples simultaneously, limited access to molecular pathologists experienced in curating both somatic and germline cancer gene variants, and a potentially longer, more complicated consent process.…”