Table 9.
Colorectal cancer susceptibility genes/loci.
| Location | Suggested Genes in or Near the Loci/variant | References | Method | Material | Hypothesis/conclusion | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1p36.13 | PLA2G2A | [41] | Genotyping (PLA2G2A specific), sequencing and LOH (loss of heterozygozity) analysis | Sporadic CRC and FAP cases | PLA2G2A mutation1 identified in one CRC patient | ||||||
| 1 | EXO1 | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 1 associated with CRC in colon/breast cancer3 oligopolyposis4 and multiple cancer5 cases | ||||||
| 1q41 | DUSP10 | [21] | Meta-analysis of 3 GWAS | CRC cases | Common low risk variants6 at 1q41 associated with CRC | ||||||
| 2p25.1 | ODC1 | [43] | Genotyping, self-administered questionnaires and cell line experiments | Sporadic CRC cases | Homozygous for the A-allele7 and use of aspirin associated with decreased risk for adenoma recurrence8 | ||||||
| 3p24.1 | TGFBR2 | [44] | PCR (polymerase chain reaction) and sequencing (TGFBR2 specific) | MSS CRC cases | TGFBR2 mutation identified in one hereditary MSS CRC patient9 | ||||||
| 3q29 | MFI2 | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 3 associated with CRC in oligopolyposis cases10 | ||||||
| 3q26.2 | MYNN | [21] | Meta-analysis of 3 GWAS | CRC cases | Common low risk variant11 associated with decreased CRC risk | ||||||
| 4 | - | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 4 associated with CRC12 | ||||||
| Location | Suggested Genes in or Near the Loci/variant | References | Method | Material | Hypothesis/conclusion | ||||||
| 4q31.3 | TLR2 | [45] | Genotyping/allele frequency (TLR2/TLR4 specific) | Sporadic CRC cases | Short-sized and long-sized13 TLR2 alleles14 associated with CRC | ||||||
| 5 | - | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 5 associated with CRC in multiple cancer cases15 | ||||||
| 6p12.3 | PKHD1 | [46] | Genotyping (T36M PKHD1 mutation specific) | CRC cases | T35M PKHD1 mutation protects against CRC | ||||||
| 7 | - | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 7 associated with CRC16 | ||||||
| 8q23.3 | EIF3H | [47] | GWAS | CRC cases17 | Common low risk variant18 associated with CRC19 | ||||||
| 8q24 |
POU5F1P120 DQ51589721 |
[48] | GWAS | CRC cases22 | Common low risk variant23 associated with CRC | ||||||
|
POU5F1P120 MYC |
[49] | Genotyping (8q24 specific) | CRC cases (multinational) | Common low risk variants24 associated with CRC | |||||||
|
DQ51589721 DQ48651321 CB10482625 POU5F1P120 POU5F120 MYC |
[50] | GWAS (confirmed by sequencing) | Familial colorectal tumour cases (replication study: CRC cases) | Common low risk variant26 associated with colorectal adenomas and cancer | |||||||
|
DQ51589721 DQ48651321 MYC |
[51] | GWAS | CRC cases (multinational) | Common low risk variant27 associated with CRC | |||||||
| - | [47] | GWAS | CRC cases17 | Common low risk variant28 associated with CRC | |||||||
| 9q22.33 |
TGFBR1 PTCH XPA |
[52] | Linkage analysis (9q specific) and LOH analysis | Family with hereditary CRC | Autosomal dominant CRC linkage to 9q22.32-31.2 | ||||||
|
SYK PTCH XPA |
[53] | Linkage analysis | Familial cases with CRC and/or advanced adenomas | Autosomal dominant CRC/advanced adenoma linkage to 9q22.2-31.2 | |||||||
| TGFBR1 | [54] | Genotyping (for germline allele-specific expression (ASE) of TGFBR1) | MSS CRC cases | Autosomal dominant ASE of TGFBR1 associated with MSS CRC | |||||||
| GALNT12 | [55] | Sequencing (of GALNT12 specific) | MSS colon cancer cell lines and CRC cases | Uncommon germline and somatic GALNT12 variants associated with late onset CRC29 | |||||||
| 9q33.1 | TLR4 | [45] | Genotyping/allele frequency (TLR2/TLR4 specific) | Sporadic CRC cases | TLR4 mutation30 associated with CRC | ||||||
| 10p14 | - | [47] | GWAS | CRC cases17 | Common low risk variant31 associated with decreased CRC risk32 | ||||||
| Location | Suggested Genes in or Near the Loci/variant | References | Method | Material | Hypothesis/conclusion | ||||||
| 11q13.3 | CCND1 | [56] | Genotyping/allele frequency (CCND1 specific) | CRC cases (multiethnic population) | CCND1 870A allele33 associated with CRC34 | ||||||
| [57] | Genotyping/allele frequency (CCND1 specific) | CRC cases (<60 years old) | CCND1 870A allele33 associated with CRC in a recessive disease model | ||||||||
| 11q23 |
LOC120376 (COLCA2) FLJ45803 (COLCA1) C11orf53 POU2AF1 |
[48] | GWAS | CRC cases22 | Common low risk variant35 associated with CRC36 | ||||||
| 12 | - | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 12 associated with CRC37 | ||||||
| 12q13.13 |
LARP4 DIP2B ATF1 |
[21] | Meta-analysis of 3 GWAS | CRC cases | Common low risk variants associated with increased38 and decreased39 CRC risk | ||||||
| 12q24.33 | POLE | [58] | Whole genome sequencing, linkage and association analysis | Large families with CRC/multiple adenomas40 | Dominantly inherited, high penetrance variant41 associated with MSS adenomas/CRC42 | ||||||
| 13q13.1 | BRCA2 | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 13 associated with CRC in breast/colon cancer cases43 | ||||||
| 13q31 |
KLF5 KLF12 LMO7 C13orf7 - (RNF219) SPRY2 GPC5 MYCBP2 POU4F1 |
[59] | Linkage analysis, LOH analysis sequencing. | Large family with hereditary CRC | Locus on chromosome 13q22.1-13q31.3 associated with CRC and adenomatous polyps in an autosomal dominant disease model44 | ||||||
| 14q22.2 | BMP4 | [20] | Meta-analysis of 2 GWAS | CRC cases | Common low risk variant45 associated with increased CRC risk46 | ||||||
| 14q32.12 | GOLGA5 | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 14 associated with CRC in oligopolyposis cases47 | ||||||
| 15q |
GREM1(part of CRAC1) SCG5 (part of CRAC1) |
[60] | Genotyping (CRAC1 specific) | Familial/early onset CRC cases48 | Common low risk variant49 associated with CRC | ||||||
| CRAC1 | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Locus at chromosome 15 associated with CRC in oligopolyposis50 and young CRC onset51 cases | |||||||
| FMN1 | [61] | GWAS and linkage analysis | Prostate cancer families with colon cancer | Linkage to cancer at 15q11-14 in families with both prostate and colon cancer | |||||||
| CRAC1 | [47] | GWAS | CRC cases17 | Common low risk variant52 associated with CRC | |||||||
| 16 | - | [42] | Genotyping | Sib pairs with CRC (divided in subgroups)2 | Loci at chromosome 16 associated with CRC in oligopolyposis cases53 and CRC in all groups54 | ||||||
| Location | Suggested Genes in or Near the Loci/variant | References | Method | Material | Hypothesis/conclusion | ||||||
| 17p13.3 | HIC1 | [42] | Genotyping | Siblings with CRC (divided in subgroups)2 | Locus at chromosome 17 associated with CRC in breast/colon cancer cases55 | ||||||
| 16q22.1 | CDH1 | [20] | Meta-analysis of 2 GWAS | CRC cases | Common low risk variant56 associated with decreased CRC risk | ||||||
| 18q21.1 | SMAD7 | [48] | GWAS | CRC cases22 | Common low risk variant57 associated with CRC | ||||||
| [47] | GWAS | CRC cases17 | Common low risk variants58 associated with CRC | ||||||||
| [62] | GWAS supported by sequencing | Familial colorectal tumour cases | Common low risk variants59 associated with CRC | ||||||||
| 19q13.33 | RHPN2 | [20] | Meta-analysis of 2 GWAS | CRC cases | Common low risk variant60 associated with decreased CRC risk32 | ||||||
| POLD1 | [58] | Whole genome sequencing, linkage and association analysis | Large families with CRC/multiple adenomas40 | Dominantly inherited, high penetrance variant61 associated with MSS, CIN+ adenomas/CRC’s62 | |||||||
| 20p12.3 | BMP2 | [20] | Meta-analysis of 2 GWAS | CRC cases | Common low risk variants63 associated with increased CRC risk32 | ||||||
| 20q13.33 | LAMA5 | [21] | Meta-analysis of 3 GWAS | CRC cases | Common low risk variant64 associated with decreased CRC risk | ||||||
| 21 | - | [42] | Genotyping | Siblings with CRC (divided in subgroups)2 | Two loci at chromosome 21 associated with CRC in breast/colon cancer cases65 | ||||||
| 22q12.1 | CHEK2 + | [63] | Allele-specific oligo-hybridization assay (for CHEK2 mutation) | Hereditary CRC cases66 | Low-penetrance variant67 associated with CRC (in families with breast and colorectal cancer) | ||||||
| [64] | Restriction fragment length polymorphism (for CHEK2 – I157T variant) | CRC cases68 | Risk allele (Il57T) for both familial and sporadic CRC and for multiple cancer types | ||||||||
1 Deletion at genomic position 11119 (codon 48) in exon 3; 2 Subgroups: 1) young age of onset, 2) breast and colon cancer, 3) multiple colorectal adenomas (oligopolyposis), 4) multiple cancers, 5) severe histopathology; 3 Flanked by polymorphic dinucleotide repeat markers: D1S1588 and D1S534; 4 Flanked by polymorphic dinucleotide repeat markers: D1S549 and D1S1609; 5 Polymorphic dinucleotide repeat marker: D1S1665; 6 SNP: rs6687758 and rs6691170; 7 SNP in Intron 1 +A316G of ODC1; 8 The two risk factors acting independently; 9 In a HNPCC-like family; 10 Flanked by polymorphic dinucleotide repeat markers: D3S2427 and D3S1311; 11 SNP: rs10936599; 12 Polymorphic dinucleotide repeat marker: D4S2366; 13 Short sized <18 GT repeats and long sized 19-25 GT repeats; 14 100 basepair upstream of the TLR2 translational start site in intron 2; 15 Flanked by polymorphic dinucleotide repeat markers: D5S2500 and D5S1725; 16 Polymorphic dinucleotide repeat marker: D7S3070; 17 Phase 1: familial colorectal tumour cases, phase 2-4: CRC cases; 18 SNP: rs16892766; 19 In a dose-dependent manner (effect significantly stronger in younger cases); 20 Pseudogene; 21 mRNA, corresponding to DNA sequence located at 8q24.21; 22 Phase 1: early onset Scottish CRC cases, phase 2: Scottish CRC cases, phase 3: multinational CRC cases; 23 SNP: rs7014346; 24 SNPs: rs6983267, rs10808556 and rs7013278; 25 Non-coding RNA corresponding to DNA sequence located at 8q24.21; 26 SNP: rs6983267; 27 SNPs: rs10505477 and rs6983267; 28 SNP: rs6983267, identified in phase 1; 29 Germline GALNT12 mutations: M1l (start codon) ATG>ATA, T491M, R297W, Y395X, R373H and R382H, somatic GALNT12 mutations: C479F and E341D; 30 Asp299Gly; 31 SNP: rs10795668; 32 In a dose dependent manner; 33 Codon 242; 34 With gene-dosage effect, association stronger for advanced stage disease and for rectal cancer; 35 SNP: rs3802842; 36 Greater risk for rectal than colon cancer and significantly differences in risk observed among European and Japanese cases; 37 No marker given; 38 SNP: rs7136702; 39 SNP: rs11169552; 40 Validated in cases with familial CRC/multiple adenomas and early onset; 41 POLE l424V; 42 Multiple or very large adenoma/CRC phenotype or early onset CRC’s; 43 Marker D12S1493; 44 Gain of chromosome 13q identified in selected cases; 45 SNP: rs4444235; 46 In a dose-dependent manner supporting a multiplicative model, association significantly stronger in MSS tumours compared to MSI; 47 Flanked by polymorphic dinucleotide repeat markers c14S1937 and D14S1436; 48 Stage 1: CRC cases selected for family history and/or early onset CRC, stage 2-3: CRC cases; 49 SNPs: rs4779584 and rs10318; 50 Flanked by polymorphic dinucleotide repeat markers D15S165 and D15S1012; 51 Polymorphic dinucleotide repeat marker D15S165; 52 SNP rs4779584, identified in phase 1 and 2; 53 Flanked by polymorphic dinucleotide repeat markers D16S540 and D16S539; 54 Polymorphic dinucleotide repeat marker D16S3019 and an unnamed marker; 55 Polymorphic dinucleotide repeat marker: D17S1308; 56 SNP: rs9929218, some evidence for association with gender - more common in females than males; 57 SNP: rs4939827, greater risk for rectal than colon cancer (no heterozygosity observed across study populations); 58 SNPs: rs4939827, rs12953717 and rs4464148, identified in phase 1, familial CRC cases; 59 SNPs: rs4939827, rs12953717 and rs4464148; 60 SNP: rs10411210; 61 S478N; 62 Multiple or very large adenoma/CRC phenotype or early onset CRC’s, also predisposition to endometrial cancer and perhaps brain tumours; 63 SNP: rs961253; 64 SNP: rs4925386; 65 One locus flanked polymorphic dinucleotide repeat markers D21S1432 and D21S1440 and one at polymorphic dinucleotide repeat marker D21S446; 66 FAP, HNPCC-like and breast cancer cases; 67 110delC; 68 Sporadic and familial, Finnish population