Biallelic Loss in DDR Genes and Its Clinical Impact

Research presented during ASCO GU 2026, showed that germline DDR variants are common enough in metastatic prostate cancer to matter clinically, but their impact is highly gene-specific.In this 3,005-patient cohort, about 9% carried a germline DDR variant, and the study was especially important because it assessed both small variants and structural variants across 31 genes.

BRCA2 is the clearest example of a germline DDR gene that tracks with truly aggressive prostate cancer. In this cohort, BRCA2 carriers were not only more common than carriers of the other genes discussed, but they also had worse pathology at diagnosis, faster movement toward castration resistance, and shorter survival. The point is not just that BRCA2 is “positive”; it is that BRCA2 often behaves like a driver of a more dangerous disease state, especially when the tumor has lost the second copy of the gene as well, which happened in 93% of the samples in this cohort.

ATM is different. It still matters, because the tumor often shows biallelic inactivation (in 100% of the samples considered for this study) meaning the inherited ATM variant is usually followed by somatic loss of the remaining normal allele.That is important biologically: once both copies are gone, the tumor is much more likely to depend on the DDR defect, which makes ATM a real cancer gene rather than a background hereditary finding.

But ATM does not seem to carry the same uniformly severe clinical signal as BRCA2. The poster did not show the same strong survival separation for ATM that it did for BRCA2, and that is consistent with the broader literature, where ATM-associated prostate cancer often looks heterogeneous in prognosis and treatment response. So the clean way to read it is this: BRCA2 is the more powerful marker of aggressive biology, while ATM is a meaningful DDR alteration that still deserves attention because of its biologic activity and possible therapeutic relevance, but it should not be interpreted as a BRCA2 equivalent.

The biallelic point is the bridge between the two. If a germline variant is found and the tumor also loses the other allele, that usually means the gene is functionally knocked out in the cancer. For BRCA2, that fits the aggressive phenotype very well; for ATM, it supports clinical relevance even when the prognostic effect is less dramatic.

The other implication of this study is technical: germline testing needs to capture structural variants. Structural events contributed meaningfully in genes such as MSH2/MSH6 and FANCA, so narrower testing could miss important hereditary findings. That matters for diagnosis, family counseling, and the accurate classification of a patient’s inherited cancer risk.

The broader takeaway is that DDR genes should not be treated as interchangeable. BRCA2, ATM, CHEK2, PALB2, and mismatch repair genes can differ in how often they undergo biallelic somatic loss and in how strongly they associate with aggressive disease. In metastatic prostate cancer, the practical message is that broader germline testing and careful gene-by-gene interpretation are essential.

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