Table 1.

Association between deficiencies in tumor DNA repair and immunotherapy response

DNA repair pathwayCommon tumor settingsClinical diagnostic criteriaHistopathologic featuresGenomic biomarkersClinical ICB response
O6-methylguanine–DNA methyltransferase (MGMT)Glioblastoma multiforme (GBM): ∼35% with MGMT promoter methylation (varies widely across clinical contexts)methylation-specific PCRMGMT promoter methylation enriched in CpG island methylator phenotype (G-CIMP) subtypeSeveral clinical trials of temozolomide and ICB are under way in GBM
Mismatch repair (MMR)Colon: ∼20% (varies widely by stage, anatomic location)Germline sequencing (Lynch syndrome)immune cell infiltrate (↑ CD8+ T cells, Th1 cells)↑ mutational burden, ↑ predicted neoantigensImproved response to PD-1 blockade (NCT01876511).
Endometrial: ∼20% (highest in endometrioid subtype)IHC (MSH2, MSH6, MLH1, PMS2)Increased PD-1, PD-L1 stainingMMR mutational signature(s)Several clinical trials of ICB in MMR-deficient tumors are planned or under way
Gastric: 15%–20% (highest rates in Western countries)MSI PCR (Bethesda assay)↑ expression of immune-related genes (PD-1, PD-L1, LAG3, CTLA-4)
Ovarian: 10% (mostly associated with Lynch syndrome, usually clear cell and endometrioid histology)
Prostate, breast, glioma: 0%–5%
Occasional cases in other tumor types
Homologous recombination (HR)Ovarian: ∼50%Germline/somatic sequencing of HR genes (BRCA1, BRCA2, PALB2, etc.)Immune cell infiltrate (↑ CD3+ and CD8+ T cells)transcriptomic HR deficiency (HRD) scores: HRD-LOH, HDR-TAI, HDR-LSTSeveral clinical trials of ICB in HR-deficient tumors are planned or under way
Breast: 10%–40% (varies by subtype)↑ PD-1, PD-L1 staining↑ mutation burden, ↑ predicted neoantigensWhether HR deficiency augments response to ICB remains to be determined
Prostate: 15%–25% in metastatic castration-resistant tumorsHR mutational signature
Other tumor types (pancreatic, gastric, endometrial)↑ cytotoxic T-cell gene signature
Polymerase (POLE/POLD1) proofreadingEndometrial: 5%–10%None in routine useImmune cell infiltrate (↑ CD3+ and CD8+ T cells)Somatic point mutation in exonuclease domain of POLE or POLD1Case reports of extreme responders
Colon: 2%–5%↑ PD-1, PD-L1 staining↑ mutational burden, ↑ predicted neoantigensPOLE-mutant tumors are being included with MMR-deficient tumors in several planned or ongoing ICB trials
Rare cases in other tumor types. Germline POLD1 and POLE mutations have been associated with a high risk of multiple colorectal adenomas and carcinomas, whereas germline POLD1 mutations also predispose to endometrial cancers.POLE/POLD1 mutational signatures
↑ cytotoxic T-cell gene signature
Nucleotide excision repair (NER)Bladder: 15%–20% of primary muscle-invasive tumorsNone in routine useNone described to dateIncreased mutational burdenNot reported
ERCC2-related mutational signature
Somatic mutation in ERCC2 or other NER gene(s)
Base excision repair (BER)Biallelic germline mutations in MUTYH are associated with increased risk of colorectal cancerNone in routine useProminent immune cell infiltrate (CD3+, CD8+, NK cells, granzyme B)BER mutational signatureNot reported
Biallelic MUTYH mutations