Table 3.
Characteristics and results of key published studies on multigene germline testing for CRC predisposition.
| Study | Tested patients | Country | Multigene panel | Hereditary CRC genes | Other cancer genesa |
|---|---|---|---|---|---|
| Non-selected CRC patients | |||||
| Yurgelun 2017 [2] | 1,058 CRC patients (clinic-based) | USA | Commercial 25-gene panelb |
High penetrance 3.1% MMR gene (Lynch sd.) 0.5% APC 0.3% biallelic MUTYH Moderate/Low penetrance 1.7% monoallelic MUTYH 1.3% APC*I1307K 0.2% CHEK2 |
High penetrance 1.0% BRCA1/2 0.2% PALB2 0.1% CDKN2A 0.1% TP53 Moderate/Low penetrance 0.9% ATM 0.3% BRIP1 0.2% NBN 0.1% BARD1 |
| AlDubayan 2018 [3] | 680 CRC patients (NHS, HPFS, CanSeq study) | USA | 14 CRC-risk genes and 40 DNA repair genes associated with (non-CRC) cancer phenotypes |
High penetrance 0.6% MMR gene (Lynch sd.) 0.3% APC 0% biallelic MUTYH Moderate/Low penetrance 1.62% monoallelic MUTYH 1.18% APC*I1307K 0.6% CHEK2 |
High penetrance 0.7% BRCA1/2 0.4% PALB2 0.3% TP53 Moderate/Low penetrance 0.7% ATM 0.3% BRIP1 0.1% BARD1 |
| DeRycke 2017 [4] | 548 CRC patients (Colon Cancer Family Registry) | Australasia USA Canada | 36-gene custom panelc (known or putative CRC genes) |
High penetrance 6% MMR gene (Lynch sd.) 0.9% APC 0.4% biallelic MUTYH Moderate/Low penetrance 0.4% CHEK2 |
High penetrance 0.2% TP53 0.5% FLCN |
| Non-selected young-onset CRC patients | |||||
| Pearlman 2017 [5] | 450 CRC patients age <50 | USA | Commercial 25-gene panelb |
High penetrance 8.4% MMR gene (Lynch sd.) 1.3% APC 0.9% biallelic MUTYH 0.2% SMAD4 Moderate/Low penetrance 1.6% monoallelic MUTYH 0.9% APC*I1307K 0.2% CHEK2 |
High penetrance 1.3% BRCA1/2 0.4% PALB2 0.2% CDKN2A Moderate/Low penetrance 0.9% ATM |
| DeRycke 2017 [4] | 333 CRC patients age ≤50 (MMR-proficient or unknown MMR status) | Australasia USA Canada | 36-gene custom panelc (known or putative CRC genes) |
High penetrance 4.8% MMR gene (Lynch sd.) 2.1% APC 1.5% biallelic MUTYH 0.3% SMAD4 0.3% BMPR1A Moderate/Low penetrance 0.3% CHEK2 |
High penetrance 0% TP53 |
| High-risk patients (familial CRC) | |||||
| Yurgelun 2015 [44] | 1,260 patients referred for Lynch sd. germline testing | USA | Commercial 25-gene panelb |
High penetrance 9.0% MMR gene (Lynch sd.) 0.4% APC 0.2% biallelic MUTYH 0.08% STK11 Moderate/Low penetrance 2.1% monoallelic MUTYH 0.4% CHEK2 |
High penetrance 1.2% BRCA1/2 0.08% PALB2 Moderate/Low penetrance 0.7% ATM 0.2% BRIP1 0.08% NBN 0.08% BARD1 0.08% RAD51C |
| Stoffel 2018 [6] | 430 CRC patients age <50 evaluated by a clinical genetics service | USA | Germline DNA sequencing (n=293) Commercial multigene panel (n=22)b 67-gene custom panel (n=117)d |
High penetrance 13.0% MMR gene (Lynch sd.) 2.3% APC 1.9% biallelic MUTYH 0.5% SMAD4 0.2% POLE Moderate/Low penetrance 0.5% CHEK2 |
High penetrance 0.5% TP53 0.2% BRCA1/2 |
| Hansen 2017 [131] | 274 patients (263 families) fulfilling the Amsterdam (n=262) or revised Bethesda (n=12) criteria with no pathogenic MMR mutations | Norway Australia | 122-gene custom paneld |
High penetrance 1.14% MMR gene (Lynch sd.)e 0.8% POLE 0.4% biallelic MUTYH 0.4% PTEN 0.4% AXIN2 (oligodontia-CRC sd.) 0% APC Moderate/Low penetrance 1.5% monoallelic MUTYH 0.4% CHEK2 |
High penetrance 1.1% BRCA1/2 Moderate/Low penetrance 0.8% ATM |
a.
The causal role of these genes in CRC predisposition has not been unequivocally proven.
b.
NTHL1, MSH3, POLE and POLD1 and RPS20 are not included in the panel.
c.
NTHL1, POLE and POLD1 and RPS20 are not included in the panel.
d.
NTHL1 and RPS20 are not included in the panel.
e.
Previously identified MMR mutation carriers had been excluded from the analysis.