Table 1.
Pathogenic replicative polymerase mutations.
| Amino Acid Change 1 | Somatic/Germline | Cancer Type 2 (n) 3 | Mutator Phenotype in Yeast [References] | Biochemical Support/Enzyme [References] |
|---|---|---|---|---|
| POLD1- | ||||
| D316G | Germline [86] | CRC, EC, and breast | Yes [87] | Yes/T4 polymerase [88] |
| D316H | Germline [86] | CRC and breast | Yes [87] | Yes/T4 polymerase [88] |
| P327L | Germline [83] | None, patient had multiple colonic adenomas | Yes 5 [89] | Yes/human Polε [45] |
| R409W | Germline [86] | CRC | N.d. | N.d. |
| L474P | Germline [86] | CRC and EC | Yes [87] | Yes/human Polε [45] |
| S478N | Germline [83] | CRC and EC | Yes [83] | N.d. |
| POLE- | ||||
| W347C | Germline [85] | Cutaneous melanoma | Yes [85] | N.d. |
| N363K | Germline [90] | CRC and EC | N.d. | N.d. |
| D368V | Germline [91] | CRC | N.d. | Yes/T4 polymerase [88] |
| P436S | Germline [92] | CRC | N.d. | N.d. |
| Y458F | Germline [93] | CRC | N.d. | Yes/T4 polymerase [88] |
| L424V/I | Both [83] | Hereditary CRC, EC (2) 4, breast (1) 4 | Yes 6 [87] | Yes/human Polε [45] |
| P286R/L/H | Somatic | CRC (5), EC (10), breast (1), stomach (1), pancreas (1) | Yes [89] | Yes/human Polε [45] |
| F367S | Somatic | CRC (1) | N.d. | Yes/human Polε [45] |
| V411L | Both [84] | CRC (3), EC (6), stomach (1) | N.d. | Yes/human Polε [45] |
| S459F | Somatic | CRC (4) | N.d. | Yes/human Polε [45] |
| S297F | Somatic | EC (1), cervical (1) | N.d. | N.d. |
| P436R | Somatic | CRC (1) | N.d. | Yes/human Polε [45] |
| M444K | Somatic | EC (1) | N.d. | N.d. |
| A456P | Somatic | EC (1) | N.d. | N.d. |
Colorectal cancer (CRC), endometrial cancer (EC), not determined (N.d.). 1 The somatic POLE exonuclease domain mutations listed have been implicated in CRC and EC tumorigenesis due to their presence in hypermutated MSI-stable and MSI-low tumors. The POLE and POLD1 mutations that predispose to CRC are from references [83,84,86,90,91,92,93,94]; 2 The incidence of mutations in different types of sporadic tumor (n) is from cBioportal and summarizes TCGA provisional data and those from published studies from other institutes; 3 For a more detailed account of incidence of germline POLE and POLD1 mutations and patient phenotype, please see [95]; 4 Though POLE-L424V is the most common mutation that predisposes to CRC, one EC and one breast cancer tumor with the L424V mutation are not hypermutated; 5 Evidence for these alleles producing a mutator phenotype is inferred from studies of yeast Polε; 6 Evidence for these alleles producing a mutator phenotype is inferred from studies of yeast Polδ.