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Updated: Oct 21, 2025
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Homologous Recombination Deficiency Alterations in Colorectal Cancer: Clinical, Molecular, and Prognostic
Roberto Moretto1, Andrew Elliott2, Jian Zhang2
1Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
Background:
Tumors with homologous recombination deficiency (HRD) show high sensitivity to platinum salts and poly(ADP-ribose) polymerase-inhibitors in several malignancies. In colorectal cancer (CRC), the role of HRD alterations is mostly unknown.
Methods:
Next-generation sequencing, whole transcriptome sequencing, and whole exome sequencing were conducted using CRC samples submitted to a commercial Clinical Laboratory Improvement Amendments certified laboratory. Tumors with pathogenic and/or presumed pathogenic mutations in 33 genes involved in the homologous recombination pathway were considered HRD, the others were homologous recombination proficient (HRP). Furthermore, tumor samples from patients enrolled in the phase III TRIBE2 study comparing upfront FOLFOXIRI+bevacizumab vs FOLFOX+bevacizumab were analyzed with next-generation sequencing. The analyses were separately conducted in microsatellite stable or proficient mismatch repair (MSS/pMMR) and microsatellite instable-high or deficient mismatch repair (MSI-H/dMMR) groups. All statistical tests were 2-sided.
Results:
Of 9321 CRC tumors, 1270 (13.6%) and 8051 (86.4%) were HRD and HRP, respectively. HRD tumors were more frequent among MSI-H/dMMR than MSS/pMMR tumors (73.4% vs 9.5%; P < .001; q < 0.001). In MSS/pMMR group, HRD tumors were more frequently tumor mutational burden high (8.1% vs 2.2%; P < .001; q < 0.001) and PD-L1 positive (5.0% vs 2.4%; P < .001; q = 0.001), enriched in all immune cell and fibroblast populations and genomic loss of heterozygosity-high (16.2% vs 9.5%; P = .03). In the TRIBE2 study, patients with MSS/pMMR and HRD tumors (10.7%) showed longer overall survival compared with MSS/pMMR and HRP tumors (40.2 vs 23.8 months; hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.45 to 0.98; P = .04). Consistent results were reported in the multivariable model (HR = 0.67, 95% CI = 0.45 to 1.02; P = .07). No interaction effect was evident between homologous recombination groups and treatment arm.
Conclusions:
HRD tumors are a distinctive subgroup of MSS/pMMR CRCs with specific molecular and prognostic characteristics. The potential efficacy of agents targeting the homologous recombination system and immune checkpoint inhibitors in this subgroup is worthy of clinical investigation.
Insights
Homologous recombination deficiency (HRD) is identified in 13.6% of colorectal cancers (CRCs), particularly in microsatellite instable-high tumors. HRD-positive MSS/pMMR CRCs show improved survival, suggesting potential therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Homologous recombination deficiency (HRD) predicts sensitivity to platinum-based chemotherapy and PARP inhibitors in various cancers.
- The role and prevalence of HRD in colorectal cancer (CRC) remain largely uncharacterized.
Purpose of the Study:
- To investigate the prevalence and characteristics of HRD in colorectal cancer (CRC).
- To evaluate the prognostic significance of HRD in CRC, particularly in the context of microsatellite stable/proficient mismatch repair (MSS/pMMR) tumors.
Main Methods:
- Utilized next-generation sequencing (NGS), whole transcriptome sequencing, and whole exome sequencing on 9321 CRC samples.
- Defined HRD based on pathogenic mutations in 33 homologous recombination pathway genes; HRD tumors were compared with homologous recombination proficient (HRP) tumors.
- Analyzed tumor samples from the phase III TRIBE2 study (FOLFOXIRI+bevacizumab vs. FOLFOX+bevacizumab) in MSS/pMMR and MSI-H/dMMR subgroups.
Main Results:
- HRD was identified in 13.6% (1270/9321) of CRC tumors.
- HRD tumors were significantly more frequent in MSI-H/dMMR (73.4%) compared to MSS/pMMR (9.5%) CRCs.
- In the MSS/pMMR subgroup, HRD tumors exhibited higher tumor mutational burden, PD-L1 positivity, immune cell enrichment, and genomic loss of heterozygosity.
- Patients with MSS/pMMR HRD tumors in the TRIBE2 study demonstrated longer overall survival (40.2 months) compared to MSS/pMMR HRP tumors (23.8 months).
Conclusions:
- HRD defines a distinct subgroup of MSS/pMMR colorectal cancers with unique molecular and prognostic features.
- HRD-positive MSS/pMMR CRCs warrant further clinical investigation for targeted therapies, including those targeting the homologous recombination system and immune checkpoint inhibitors.
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