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  • How Germline DNA-Repair Variants May Influence the Intratumoral Microbiome in Breast Cancer: An Emerging Mechanistic Hypothesis

  • Melika Mollahoseini ,1,*


  • Introduction: Introduction Inherited pathogenic variants in DNA repair genes are important determinants of breast cancer susceptibility and tumor biology. BRCA1 and BRCA2 are central to homologous-recombination (HR) mediated repair of DNA double strand breaks, whereas PALB2 coordinates BRCA1–BRCA2–RAD51 function. ATM and CHEK2 participate in DNA damage sensing and checkpoint control, while RAD51C and RAD51D contribute to HR and hereditary breast ovarian cancer susceptibility. Defects in these pathways can result in homologous recombination deficiency (HRD), replication stress, chromosomal instability, and characteristic genomic alterations. However, the biological and clinical consequences are gene and allele dependent ; importantly, the presence of a germline pathogenic variant should not automatically be interpreted as evidence of HRD in every tumor. The breast cancer intratumoral microbiome has emerged as a distinct and increasingly investigated dimension of tumor biology. Recent studies and reviews have reported microbial signatures within breast tumors and potential associations with immune cell states, host metabolism, tumor progression, and treatment response. These findings challenge the traditional view of breast tumors as microbiologically sterile. However, interpretation remains complicated by low microbial biomass, potential contamination, differences in tissue sampling, and variation in sequencing and decontamination approaches. The central question is therefore not simply whether DNA repair variants and tumor associated microbes are each relevant to breast cancer, but whether germline DNA repair status may influence the composition, abundance, or persistence of specific intratumoral microbes through genomic, metabolic, inflammatory, or immune mechanisms. Current literature does not yet establish a direct causal relationship between germline DNA repair genotype and the intratumoral microbiome. This narrative review integrates the available evidence, distinguishes established findings from mechanistic inference, identifies the major knowledge gap, and proposes priorities for testing this emerging connection in future cancer-genetics and multi omics studies.
  • Methods: Methods A narrative literature review was conducted to integrate evidence across three interconnected domains: germline DNA repair variants in breast cancer, homologous recombination deficiency and genomic instability, and the intratumoral microbiome of breast cancer. Literature searches were performed in PubMed/MEDLINE using combinations of terms related to BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C, RAD51D, DNA repair, HRD, genomic instability, breast cancer, intratumoral microbiome, and tumor-associated microbiota. Recent literature was prioritized, while landmark studies were retained when necessary to establish established genetic or biological concepts. Peer reviewed primary studies, mechanistic studies, and relevant focused reviews were considered. Preprints were excluded where publication type filters were available. Because the available studies differed substantially in study populations, biological materials, microbiome profiling methods, germline genotype definitions, contamination controls, and outcome measures, quantitative meta analysis was not considered appropriate. The evidence was synthesized thematically and classified into three categories: established component evidence, supported directly by breast cancer studies or relevant genetic models; indirect evidence, derived from related cancer types, treatment settings, or host microbiome studies; and mechanistic hypotheses, representing biologically plausible relationships that have not yet been directly tested in breast cancer patients stratified by germline DNA repair genotype. The literature was specifically assessed for evidence directly linking germline DNA repair variants with intratumoral microbiome composition or function. Particular attention was given to methodological limitations relevant to low biomass microbiome research, including contamination, tissue sampling, sequencing methodology, and microbial signal validation. No quantitative effect estimates were pooled because the available evidence was heterogeneous and insufficient for formal meta analysis. Scopus and Web of Science searches should be completed and documented before final submission if required by the congress or stated in the review protocol.
  • Results: Results The retrieved literature supports a well established genetic framework linking pathogenic variants in BRCA1, BRCA2, and PALB2 to homologous recombination defects and genomic instability in breast cancer. Experimental studies further indicate that PALB2 deficiency can affect replication and DNA damage response processes. The functional interaction between BRCA1 and PALB2 provides additional biological support for the role of PALB2 in homologous-recombination repair. Studies of ATM and CHEK2 demonstrate substantial gene-specific differences in breast-cancer susceptibility and penetrance, indicating that inherited DNA repair alterations cannot be considered biologically equivalent across genes. RAD51C and RAD51D are also established hereditary cancer susceptibility genes; however, the reviewed breast cancer microbiome literature did not identify genotype resolved analyses evaluating intratumoral microbial composition in carriers of these variants. Across the retrieved literature, evidence directly linking a specific germline DNA repair genotype to a reproducible intratumoral microbiome signature in breast cancer was not identified. The available evidence therefore supports the genetic and microbiome components independently, while the proposed connection between them remains primarily mechanistic and hypothesis generating. Importantly, the available evidence does not establish that every germline DNA repair carrier develops HRD, that HRD necessarily alters intratumoral microbial colonization, or that different DNA repair gene defects produce equivalent microbial profiles. These limitations highlight a major evidence gap and support the need for genotype stratified breast cancer microbiome studies.
  • Conclusion: Conclusion Germline DNA repair variants provide a biologically plausible route through which host genotype may influence the breast cancer intratumoral microbiome through HRD, genomic instability, altered metabolism, cellular surface biology, and immune selection. Current evidence is strongest for the individual components of this framework, including hereditary DNA repair biology, tumour associated microbial signals, and host microbe interactions relevant to treatment response. However, direct evidence that BRCA1, BRCA2, PALB2, ATM, CHEK2, RAD51C, or RAD51D variants shape a reproducible intratumoral microbiome in breast cancer remains insufficient. A key priority for future research is the development of genotype- and HRD-resolved, spatially controlled, longitudinal studies capable of distinguishing inherited effects from tumour evolution, treatment exposure, contamination, and sampling bias.
  • Keywords: Keywords: Breast cancer; Germline pathogenic variants; DNA repair; BRCA1; BRCA2; PALB2

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