Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy
Abstract
:1. Introduction
2. The Fanconi Anemia Pathway in DNA Repair and Maintenance of Genome Integrity
2.1. The FA Pathway and Inter-Strand Crosslink Repair
2.2. FA Proteins Stabilize Stalled Replication Forks
3. Potential Role of FANC Gene Mutations in Colorectal Cancer Susceptibility
3.1. Germline Monoallelic Mutations
3.2. Somatic Mutations
4. FA Components as Potential Biomarkers for Predicting Disease Progression and Treatment Response
5. FA Components as Promising Therapeutic Targets in CRC
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
APC | APC regulator of WNT signaling pathway |
ATR | ataxia telangiectasia and RAd3-related kinase |
BCDX2 complex | RAD51 paralogs (RAD51B, RAD51C, RAD51D) and XRCC2 |
BMPR1A | bone morphogenetic protein receptor type 1A |
BRAF | B-Raf proto-oncogene, serine/threonine kinase |
BRCA | BRCA1 DNA repair associated (alias FANCS) |
BRCA2 | BRCA2 DNA repair associated (alias FANCD, FANCD1) |
BRIP1 | BRCA1 interacting helicase 1 (alias FANCJ) |
CHK1 | checkpoint kinase1 |
CNV | copy number variation |
CRC | colorectal cancer |
dNTP | deoxyribonucleoside triphosphate |
DSB | double-strand break |
EOCRC | early-onset CRC |
ERCC1 | ERCC excision repair 1, endonuclease catalytic subunit |
ERCC4 | ERCC excision repair 4, endonuclease catalytic subunit (alias FANCQ) |
FA | Fanconi anemia |
FAAP | RNA 2′,3′-cyclic phosphate and 5′-OH ligase |
FAAP100 | FA core complex associated protein 100 |
FAAP20 | FA core complex associated protein 20 |
FAAP24 | FA core complex associated protein 24 |
FAN1 | FANCD2 and FANCI associated nuclease 1 |
FANC | FA complementation group |
FANCA | FA complementation group A |
FANCB | FA complementation group B |
FANCC | FA complementation group C |
FANCD1 | BRCA2 DNA repair associated (official symbol BRCA2) |
FANCD2 | FA complementation group D2 |
FANCE | FA complementation group E |
FANCF | FA complementation group F |
FANCG | FA complementation group G (alias XRCC9) |
FANCI | FA complementation group I |
FANCJ | BRCA1 interacting helicase 1 (official symbol BRIP1) |
FANCL | FA complementation group L |
FANCM | FA complementation group M |
FANCN | partner and localizer of BRCA2 (official symbol PALB2) |
FANCO | RAD51 paralog C (official symbol RAD51C) |
FANCP | SLX4 structure-specific endonuclease subunit |
FANCQ | ERCC excision repair 4, endonuclease catalytic subunit (official symbol ERCC4) |
FANCR | RAD51 recombinase (official symbol RAD51) |
FANCS | BRCA1 DNA repair associated (official symbol BRCA) |
FANCT | FA complementation group T/Ubiquitin Conjugating Enzyme E2 T (official symbol UBE2T) |
FANCU | X-ray repair cross complementing 2 (official symbol XRCC2) |
FANCV | mitotic arrest deficient 2 like 2 (official symbol: MAD2L2; alias REV7) |
FANCW | ring finger and WD repeat domain 3 (official symbol RFWD3) |
FCCTX | familial CRC type X |
FOLFIRI | fluorouracil/leucovorin, irinotecan |
FOLFOX | fluorouracil/leucovorin, oxaliplatin |
G4 | G-quadruplex |
GEO | Gene Expression Omnibus |
HR | homologous recombination |
HRR | homologous recombinational repair |
ICL | inter-strand crosslink |
ID2 complex | FANCI-FANCD2 |
KRAS | Kirsten RAS proto-oncogene |
LARC | locally advanced rectal cancer |
mCRC | metastatic CRC |
MEK1 | mitogen-activated protein kinase kinase 1 (official symbol MAP2K1) |
MEK2 | mitogen-activated protein kinase kinase 2 (official symbol MAP2K2) |
MHF1 | centromere protein S (official symbol CENPS) |
MHF2 | centromere protein X (official symbol CENPX) |
MLH1 | mutL homolog 1 |
MLH2 | PMS1 homolog 1, mismatch repair system component (official symbol PMS1) |
MMR | mismatch repair, |
MRN complex | MRE11-RAD50-NBS proteins |
MSH2 | mutS homolog 2 |
MSH6 | mutS homolog 6 |
MSI | microsatellite instability |
MSS | microsatellite stability |
MUTYH | mutY DNA glycosylase |
NCI GDC | National Cancer Institute-Genomic Data Commons |
NER | nucleotide excision repair |
NGS | next-generation sequencing; |
NHEJ | non-homologous end joining |
NTHL | nth like DNA glycosylase |
PALB2 | partner and localizer of BRCA2 (alias FANCN) |
PARP1 | poly (ADP-ribose) polymerase 1 |
PARPi | PARP inhibitor |
PFS | progression-free survival |
PMS2 | PMS1 homolog 2, mismatch repair system component |
POLD1 | DNA polymerase delta 1, catalytic subunit |
POLE | DNA polymerase epsilon, catalytic subunit |
POLQ | DNA polymerase theta |
PPAP | polymerase proofreading–associated polyposis |
PPI | protein–protein interaction |
PTEN | phosphatase and tensin homolog |
PV | pathogenic variation |
RAD51 | RAD51 recombinase (alias FANCR) |
RAD51B | RAD51 paralog B |
RAD51C | RAD51 paralog C (alias FANCO) |
RAD51D | RAD51 paralog D |
REV1 | REV1 DNA directed polymerase |
REV7 | mitotic arrest deficient 2 like 2 (official symbol: MAD2L2; alias FANCV) |
RFWD3 | ring finger and WD repeat domain 3 (alias FANCW) |
RNaseH | ribonuclease H |
SMAD4 | SMAD family member 4 |
ssDNA | single-strand DNA |
STK11 | serine/threonine kinase 11 |
TLS | translesion DNA synthesis |
TMEJ | polymerase theta-mediated end joining |
TMS | telomestatin |
TNM | tumor (lymph) node metastasis staging |
TP53 | tumor protein p53 |
UBE2T | Ubiquitin Conjugating Enzyme E2 T (alias FANCT) |
VEGF | Vascular endothelial growth factor |
WES | whole-exome sequencing |
XRCC2 | X-ray repair cross complementing 2 (alias FANCU) |
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Gene(s) and No. | Study Group | Study Method | N. of FANC Gene Mutation Carriers in CRC Patients | Reference |
---|---|---|---|---|
FANCD1/BRCA2: 2 | 2 patients from 1 family, no mutations in known CRC genes | Point mutation screening of the BRCA1 and BRCA2 genes | 2/2 | [73] |
FANCD1/BRCA2: 2 | 48 FCCTX probands with strong familial CRC aggregation; no mutations in known CRC genes | Mutation screening of BRCA2 | 2/48 | [85] |
FANCD1/BRCA2: 9 FANCS/BRCA1: 6 FANCJ/BRIP1: 2 | 1260 CRC patients with suspected Lynch syndrome | 25-gene NGS panel testing | 17/1260 | [86] |
FANCS/BRCA1: 4 FANCD1/BRCA2: 1 FANCN/PALB2: 2 | 450 EOCRC patients | 25-gene NGS panel testing | 7/450 | [30] |
FANCS/BRCA1: 1 | 430 EOCRC patients < 50 years | 154-gene NGS panel testing | 1/430 | [87] |
FANCI:1, FANCL: 1 FANCO/RAD51C: 1 FANCQ/ERCC4: 1 FANCS/BRCA1: 1 FANCU/XRCC2: 1 | 330 mCRC patients age ≤ 55 years, 110 mCRC patients age > 55 years | 98-gene NGS panel testing | 6/440 | [44] |
FANCD1/BRCA2: 179 FANCS/BRCA1: 72 | 6396 unselected CRC samples | 592-gene NGS panel testing | 251/6396 | [88] |
FANCD1/BRCA2: 8 FANCJ/BRIP1: 3 FANCS/BRCA1: 3 FANCN/PALB2: 2 | 1058 unselected CRC samples | 25-gene NGS panel testing | 16/1058 | [27] |
FANCN/PALB2: 3 | 680 unselected CRC patients | 40-gene NGS panel testing | 3/680 | [72] |
FANCD1/BRCA2: 1 FANCS/BRCA1: 1 | 618 unselected CRC patients | 73-gene NGS panel testing | 2/618 | [29] |
FANCJ/BRIP1: 3 FANCD1/BRCA2: 2 FANCS/BRCA1: 2 FANCU/XRCC2: 1 | 189 unselected CRC patients | 25-gene NGS panel testing | 8/189 | [83] |
FANCD1/BRCA2: 1 FANCN/PALB2: 1 | 88 EOCRC patients ≤ 50, MMR-proficient | WES | 2/88 | [84] |
FANCD1/BRCA2: 4 FANCJ/BRIP1: 1 FANCO/RAD51C: 1 | 133 EOCRC patients < 55 years | WES | 6/133 | [89] |
FANCD1/BRCA2: 2 FANCC: 1, FANCE: 1 FANCJ/BRIP1: 1 | 74 CRC patients from 40 unrelated families with strong CRC aggregation; no mutations in known CRC genes | WES | 5/74 | [28] |
FANCM: 4 | 94 CRC patients (47 CRC-affected cousin pairs) | WES | 4/94 | [96] |
FANCA: 1 FANCD1/BRCA2: 1 FANCD2: 1, FANCM: 2 | 141 unselected CRC patients | WES | 5/141 | [31] |
FA Component | FA Component Status | Drug Treatment(s) or Synthetic Lethality Partner(s) | Study Materials | Setting | Mechanism of Action/Observed Results | Ref. |
---|---|---|---|---|---|---|
FANCR/RAD51 | RAD51 inhibition (B02 inhibitor) | Prexasertib (CHK1/2 inhibitors) | CRC stem cells | In vitro | Triggering mitotic catastrophe | [131] |
RAD51 inhibition (B02 inhibitor) | Mirin (MRE11 inhibitor) | PARP1-upregulated CRC stem cells | In vitro and in vivo | Triggering mitotic catastrophe | [129] | |
Decreased RAD51 protein | Talazoparib (PARP inhibitor) | TP53 wild-type cell lines | In vitro | Increased sensitivity to the PARP inhibitor | [132] | |
Increased RAD51 foci formation | Olaparib (PARP inhibitor) | Patient-derived CRC models | In vitro | Resistance to the PARP inhibitor | [133] | |
RAD51 inhibition (RI-1 inhibitor) | AZD6244 (MEK1/2 inhibitor) | KRAS-mutant cells | In vitro | Induction of DNA damage and apoptosis | [134] | |
RAD51 knockdown (specific siRNA) | Alpinumisoflavone (natural flavonoid) | CRC cell lines | In vitro | Increased anti-cancer activity of alpinumisoflavone | [135] | |
FANCD1/S (BRCA1/2) | BRCA1/2 depletion (specific shRNA) | Olaparib (PARP inhibitor) | BRCA-deficient cell lines | In vitro | Genomic instability and cell death | [140] |
BRCA1/2 depletion (specific shRNA) | Olaparib and talazoparib (PARP inhibitors) | BRCA-deficient cell lines | In vitro and in vivo | Elicit innate immune response | [144] | |
ND | Niraparib (PARP inhibitor) and irinotecan | MSI or MSS CRC cells | In vitro or in vivo | Enhancement of the anti-tumor effects of both agents | [143] | |
BRCA1 gene expression | POLB, CSNK1E, MSH2 | GEO datasets-mCRC patients and CRC cells | Translational and in vitro | Synthetic lethality | [145] | |
BRCA2 gene expression | MSH2 | GEO datasets-mCRC patients and CRC cells | Translational and in vitro | Synthetic lethality | [145] | |
High BRCA1 gene expression | Bevacizumab (VEGF Inhibitor) | GEO datasets-mCRC patients | Translational | More favourable PFS | [146] | |
Mutated BRCA1 | Oxaliplatin plus radiation before surgery | One LARC patient | Case report | Increased sensitivity to platinum-based chemotherapy | [148] | |
FANCU/XRCC2 | XRCC2 depletion (specific shRNA) | X-radiation | T84 colon tumor cell line | In vitro and In vivo | Increased sensitivity to X-radiation | [149] |
XRCC2 targeting by miR-7 | - | CRC cell lines | In vitro | Apoptosis and inhibition of proliferation | [151] | |
Biallelic mutated XRCC2 | Olaparib (PARP inhibitor) | Fibroblast cells | In vitro | Increased sensitivity to olaparib | [152] | |
Increased expression of XRCC2 | Olaparib (PARP inhibitor) | CRC cell lines | In vitro | Synthetic lethality | [153] | |
FANCV/REV7 | REV7 depletion (CRISPR/Cas9) | 5-fluorouracil and oxaliplatin | CRC cells | In vitro and In vivo | Impair of translesion DNA synthesis pathway | [154] |
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Parsa, F.G.; Nobili, S.; Karimpour, M.; Aghdaei, H.A.; Nazemalhosseini-Mojarad, E.; Mini, E. Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy. J. Pers. Med. 2022, 12, 396. https://doi.org/10.3390/jpm12030396
Parsa FG, Nobili S, Karimpour M, Aghdaei HA, Nazemalhosseini-Mojarad E, Mini E. Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy. Journal of Personalized Medicine. 2022; 12(3):396. https://doi.org/10.3390/jpm12030396
Chicago/Turabian StyleParsa, Fatemeh Ghorbani, Stefania Nobili, Mina Karimpour, Hamid Asadzadeh Aghdaei, Ehsan Nazemalhosseini-Mojarad, and Enrico Mini. 2022. "Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy" Journal of Personalized Medicine 12, no. 3: 396. https://doi.org/10.3390/jpm12030396