Table 5.
Germline (G) and somatic (S) mutations affecting coding (c) and non-coding (nc) regions in target genes of anticancer drugs in primary liver cancer
| Gene | Protein | Genetic mutation | G/S | Region | Protein mutation | Functional consequences | Clinical consequences | Studies | Ref. |
|---|---|---|---|---|---|---|---|---|---|
| BRAF | BRAF | c.1799A>T | S | c | Val600Glu | Moderate | Decreased OS | CCA patients | [120] |
| ND | Biliary Adenoma | [121] | |||||||
| c.1910T>A | S | c | Val637Glu | Activation of MAPK and AKT pathways | Enhanced proliferation | HCC in vivo | [122,123] | ||
| EGFR | EGFR | c.2464G>A | S | c | Ala822Pro | Moderate | ND | HCC patients | [119] |
| c.67C>T | S | c | Arg23Trp | ND | Benign | HCC patients | [119] | ||
| c.374A>G | S | c | Tyr125Cys | ND | ND | HCC patients | dbEMT | ||
| c.2165_2173
dupCCAGCGTGG |
S | c | Ala722_Val724dup | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.2095A>G | S | c | Ile699Val | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.3313A>T | S | c | Thr1105Ser | Moderate | Neutral | TCGA-LIHC | TCGA | ||
| c.1097C>G | S | c | Pro366Arg | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.926_945
delCGAATATTA AACACTTCAAA |
S | c | Thr309fs*17 | High | ND | TCGA-LIHC | TCGA | ||
| c.3349A>T | S | c | Ser1117Cys | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.1881-2577C>T | S | nc | Intron | Modifier | ND | TCGA-LIHC | TCGA | ||
| c.1072+33G>T | S | nc | Intron | Modifier | No significant | TCGA-LIHC | TCGA | ||
| FLT1 | VEGFR1 | c.2306G>A | S | c | Ala769Val | Moderate | ND | HCC patients | [119] |
| c.2196_2198delTGA | S | c | Ser733* | High | ND | HCC patients | [119] | ||
| c.2110C>T | S | c | Glu704Lys | Moderate | ND | HCC patients | [119] | ||
| c.1796C>G | S | c | Thr599Arg | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.2021delG | S | c | Ser674fs*12 | Modifier | ND | TCGA-LIHC | TCGA | ||
| c.166dupG | S | c | Glu56fs*5 | High | ND | TCGA-CHOL | TCGA | ||
| c.1988A>C | S | c | Lys663Thr | Modifier | ND | TCGA-LIHC | TCGA | ||
| c.679A>T | S | c | Asn227Tyr | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.1997A>T | S | c | Asn666Ile | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.3636-1G>C | S | nc | Splice acceptor | High | Pathogenic | TCGA-LIHC | TCGA | ||
| KDR | VEGFR2 | c.1416A>T | G | c | Gln472His | ND | Increased PFS and OS | HCC patients | [114] |
| c.713A>G | S | c | Val238Ala | ND | Benign | HCC patients | [119] | ||
| c.2935G>A | S | c | Glu979Lys | Moderate | ND | TCGA-CHOL | TCGA | ||
| c.1054G>T | S | c | Ala352Ser | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.1772T>G | S | c | Leu591Arg | Moderate | Neutral | TCGA-LIHC | TCGA | ||
| c.3944A>G | S | c | Asp1315Gly | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.1297G>T | S | c | Asp433Tyr | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.3957C>A | S | c | Tyr1319* | High | Pathogenic | TCGA-LIHC | TCGA | ||
| c.3152G>A | S | c | Arg1051Gln | Moderate | Pathogenic | TCGA-CHOL | TCGA | ||
| c.1368C>G | S | c | Ile456Met | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.2398G>C | S | c | Gly800Arg | Moderate | Pathogenic | TCGA-LIHC | TCGA | ||
| c.*172G>A | S | nc | 3´UTR | Modifier | ND | TCGA-LIHC | TCGA | ||
| VEGFA | VEGFA | c.-94C>G | G | nc | 5’UTR | ND | Decreased
PFS and OS |
HCC patients | [118] |
| c.332_346del
GCCCGGGCC TCGGGC |
S | c | Ala112_Gly116del | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.*285A>G | S | nc | 3´UTR | Modifier | ND | TCGA-CHOL | TCGA | ||
| c.308+1G>C | S | nc | Splice donor | High | ND | TCGA-LIHC | TCGA | ||
| VEGFC | VEGFC | c.986C>T | S | c | Gly329Glu | Moderate | ND | HCC patients | [119] |
| c.367C>A | S | c | Asp123Tyr | Moderate | ND | HCC patients | [119] | ||
| c.235T>C | S | c | Lys79Glu | Moderate | ND | HCC patients | [119] | ||
| c.842G>A | S | c | Gly281Glu | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.938A>G | S | c | Asn313Ser | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.341A>T | S | c | Tyr114Phe | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.1037C>G | S | c | Thr346Ser | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.1253T>G | S | c | Met418Arg | Moderate | ND | TCGA-LIHC | TCGA | ||
| c.820G>C | S | c | Asp274His | Moderate | ND | TCGA-CHOL | TCGA | ||
| c.-17C>A | S | nc | 5’UTR | Modifier | ND | TCGA-LIHC | TCGA | ||
| g.177608775T>C | S | nc | Intron | ND | Decreased
PFS and OS |
HCC patients | [118] |
Data obtained from referred literature, dbEMT, and TCGA database. Functional consequences are based on VEP (Variant Effect Predictor; https://www.ensembl.org/vep) impact: High means that the variant is supposed to cause a high disruptive impact in the protein, which is likely to cause loss of function; Moderate means that the variant may be not disruptive, but results in a decrease effectiveness of the encoded protein; Modifier is usually referred to non-coding variants, whose impact is difficult to determine, although they can be involved in transcription or splicing changes. OS: overall survival; PFS: progression-free survival; CCA: cholangiocarcinoma; HCC: hepatocellular carcinoma; IHCA: Inflammatory hepatocellular adenomas; ND: not described; TCGA: the cancer genome atlas; TCGA-LIHC: the cancer genome atlas - liver hepatocellular carcinoma; TCGA-CHOL: the cancer genome atlas - cholangiocarcinoma