Table 1:

Immunologic features of three distinct neoplastic pathways.

Germline mechanism of hypermutability	Characteristics of associated cancers	Loci of somatic hypermutations in invasive cancers	Evidence of immunogenic phenotype	Immunologic considerations in premalignant biology
DNA mismatch repair gene mutations: Lynch syndrome (LS); biallelic mismatch repair deficiency (BMMR-D)	Gl, gyn, and other cancers with high-level microsatellite instability (MSI); pediatric-onset Gl cancers, gliomas, and lymphomas in BMMR-D	Mono- and dinucleotide repeat microsatellites in non-coding and coding DNA; certain “hotspot” microsatellites within driver genes, e.g., TGFBR2 and BAX in LS; POLE or POLD1 in BMMR-D	MSI-induced frameshift neopeptides/neoantigens found in associated cancers; early success of PD-1 antibodies	Not systematically studied; MSI-H (presumably a surrogate for neoantigen load) seen in various premalignant states (adenomas, intestinal crypt foci, IPMNs, DCIS, etc.)
BRCA1/2 mutations	Breast, ovarian, pancreatic, prostate, and other cancers with homologous recombination deficiency	Specific signatures of tandem duplications and/or deletions	BRCA1/2-associated ovarian cancers demonstrate infiltrating lymphocytes and increased expression of genes related to immune-mediated cytotoxicity	Not well studied; loss of wild-type BRCA1/2 allele is seen in some premalignant lesions, but BRCA1/2 haploinsufficiency leads to increased expression of EGFR and genomic instability in non-neoplastic breast epithelium cells prior to loss of wild-type BRCA function
APOBEC3A/B chimeric deletion polymorphism	Modestly increased risk of breast (and possibly other) cancers with somatic hypermutation; increased stability of chimeric APOBEC3A/B mRNA leads to increased APOBEC3A activity correlating with germline copy number	TCA and TCG trinucleotide sequences, including certain “hotspots” within driver genes, e.g., PIK3CA	Cancers show upregulation of genes associated with immune activation, cytokine response, and lymphocytic infiltration; penetrance of immune-activating effects appears to be high	Not well studied; APOBEC3A/B-related mutational patterns seen in sporadic (i.e., not associated with germline polymorphism) pre-invasive bladder carcinoma and cervical intraepithelial neoplasia

This schematic outlines the rationale for investigating the immunobiology of premalignancy in three distinct inherited neoplastic pathways: mismatch repair deficiency, BRCA1/2 mutations, and APOBEC3A/B-mediated neoplasia. Cancers associated with all three pathways are associated with distinct, predictable forms of somatic hypermutability and have various features suggesting an immunogenic phenotype. In each case, however, an in-depth understanding of premalignant biology will be key to devising strategies for primary cancer prevention.