Open Access

Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

M Staninova-Stojovska
M Staninova-Stojovska
, 
N Matevska-Geskovska
N Matevska-Geskovska
, 
M Panovski
M Panovski
, 
B Angelovska
B Angelovska
, 
N Mitrevski
N Mitrevski
, 
M Ristevski
M Ristevski
, 
R Jovanovic
R Jovanovic
 and 
AJ Dimovski
AJ Dimovski
   | Dec 21, 2019
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Article Category: Original Article
Published Online: Dec 21, 2019
Page range: 5 - 16
DOI: https://doi.org/10.2478/bjmg-2019-0027
Keywords
© 2019 Staninova-Stojovska M, Matevska-Geskovska N, Panovski M, Angelovska B, Mitrevski N, Ristevski M, Jovanovic R, Dimovski AJ,, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

Number of patients in different subgroups based on the number of polyps and MSI status of their tumors at diagnosis. M: male; F: female; P: Proximal colon (caecum, ascendens, transversum); D: distal colon (descendens, sigma, rectum).
Number of patients in different subgroups based on the number of polyps and MSI status of their tumors at diagnosis. M: male; F: female; P: Proximal colon (caecum, ascendens, transversum); D: distal colon (descendens, sigma, rectum).

Figure 2

Distribution of deleterious variants in 66 patients with HNPCC. The distribution of the mutations in different genes in the two subgroups of HNPCC patients divided by the MSI status of their tumors is also shown.
Distribution of deleterious variants in 66 patients with HNPCC. The distribution of the mutations in different genes in the two subgroups of HNPCC patients divided by the MSI status of their tumors is also shown.

Figure 3

Distribution of deleterious variants in 41 patients with polyposis syndrome. The distribution of the mutations in different genes in the two subgroups of patients divided by the number of polyps at diagnosis is also shown.
Distribution of deleterious variants in 41 patients with polyposis syndrome. The distribution of the mutations in different genes in the two subgroups of patients divided by the number of polyps at diagnosis is also shown.

Figure 4

The overall frequency of different types of variants detected in 107 patients with hereditary CRC (A), and their distribution in different clinical subtypes of patients (B).
The overall frequency of different types of variants detected in 107 patients with hereditary CRC (A), and their distribution in different clinical subtypes of patients (B).

Figure 5

Distribution of deleterious (A) and VUS (B) in known CRC genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, NTHL1, BMPR1A, POLE), DRG genes (BRCA2, BLM, CHEK2, BRIP1, PALP2, FANCM, ATM, MRE11, FANCL, ERCC2) and other genes (FLCN, FH, KIT, CDH1, EZH2, CEP57, RUNX1).
Distribution of deleterious (A) and VUS (B) in known CRC genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, NTHL1, BMPR1A, POLE), DRG genes (BRCA2, BLM, CHEK2, BRIP1, PALP2, FANCM, ATM, MRE11, FANCL, ERCC2) and other genes (FLCN, FH, KIT, CDH1, EZH2, CEP57, RUNX1).

Summary of clinical data and molecular defects detected in 66 patients with hereditary nonpolyposis colorectal cancer.

n Sex- Age History (relatives affected) Tumor Location Stage at DX Extracolonic Cancers

G: gastric cancer; P: prostate cancer; Ur: ureteral cancer; E: endometrial cancer; B: breast cancer; O: ovarian cancer; T: thyroid cancer; L: leukemia; R: renal cancer; Br: brain tumor: no mutation detected; [-]: absent; na: not available

 Gene DNA Sequence Change Amino Acid Change ACMG Classification [11]
MSI Status MLH1 met BRAF V600E
1 M-42 1: 1st; 2: 2nd degree transversum na G; P; Ur MLH1 c.896_897insC p.Pro300SerfsTer7 pathogenic [+] [–] [–]
2 M-55 3: 1st; 1: 2nd degree transversum na none MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
3 F-49 1: 1st; 1: 2nd degree transversum

Synchronous: colon + gastric cancer, 5 years before endometrial cancer.

 IIA G; E MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
4 M-32 1: 1st; 2: 2nd degree transversum IIA none MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
5 M-33 1: 1st; 2: 2nd degree ascendens IIA none MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
6 F-48 positive family history; NS ascendens na E MLH1 c.1602del p.Asn535IlefsTer56 pathogenic [+] [–] [–]
7 F-43 2: 1st; 3: 2nd degree descendens na G; P; Ur MLH1 c.896_897insC p.Thr372ThrfsTer7 pathogenic [+] [–] [–]
8 F-60 2: 1st; 2: 2nd degree caecum IIA none MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
9 F-41 1: 1st; 2: 2nd degree caecum na E MLH1 c.1667+1del p.? pathogenic [+] [–] [–]
10 F-29 1: 1st; 2: 2nd; 2: 3rd degree descendens na none MLH1 c.392C>G p.Ser131Ter pathogenic [+] [–] [–]
11 F-24 1: 1st; 1: 2nd degree caecum IIA E MLH1 c.244A>G p.Thr82Ala likely pathogenic [+] [–] [–]
12 M-40 1: 1st degree ascendens IIA none MLH1 c.244A>G p.Thr82Ala likely pathogenic [+] [–] [–]
13 M-55 1: 2nddegree caecum IIA none MLH1 c.244A>G p.Thr82Ala likely pathogenic [+] [–] [–]
14 M-38 2: 1st; 2: 2nd; 2: 3rd degree ascendens IIA P; B MLH1 c.62C>T p.Ala21Val likely pathogenic [+] [–] [–]
15 F-57 1: 1st; 2: 2nd degree ascendens na B MLH1 c.683T>C p.Leu228Pro likely pathogenic [+] [–] [–]
16 M-15 1: 1st; 2: 2nd degree transversum IIA E MSH2 c.2211-2A>C p.? pathogenic [+] [–] [–]
17 F-41 2: 1st; 2: 2nd degree caecum IIA E MSH2 c.2211-2A>C p.? pathogenic [+] [–] [–]
18 M-50 1: 1st; 2: 2nd; 2: 3rd degree transversum IIA E MSH2 c.2211-2A>C p.? pathogenic [+] [–] [–]
19 M-41 3: 2nd degree rectosygma IIIC E MSH2 c.209_211+11del p.? pathogenic [+] [–] [–]
20 M-46 1: 1st; 4: 2nd; 2: 3rd degree rectum na G MSH2 c.1786-1788del p.Asn596del likely pathogenic [+] [–] [–]
21 F-31 1: 1st; 2: 2nd degree ascendens IVA none MSH6 c.(?_-152)_(260+1_261-1) p.? pathogenic [–] NA [–]
22 F-44 1: 1st; 2: 2nd degree rectum IIIB E MSH6 c.458+1G>T p.? pathogenic [–] NA [–]
23 F-44 2: 1st; 2: 2nd degree transversum IIIA O MSH6 c.2384T>C p.Ile795Thr VUS [–] NA [–]
24 M-81 1: 1st degree rectum IIIC none PMS2 gene inversion – pathogenic [–] NA [–]
25 M-61 1: 1st degree sygma IIIB none PMS2 gene inversion – pathogenic [–] NA [–]
26 M-31 1: 1st degree caecum IIA none PMS2 c.(803+1_804-1)_ (*1_?)del p.? pathogenic [+] [–] [–]
27 M-39 1: 1st degree ascendens IIIC E PMS2 c.(803+1_804-1)_ (*1_?)del p.? pathogenic [+] [–] [–]
28 M-68 1: 1st; 1: 2nd degree rectosygma + caecum IIA none PMS2 c.2192_2196del p.Leu731CysfsTer3 pathogenic [+] [–] [–]
29 M-65 1: 1st degree caecum na none PMS2 c.1327del p.Pro443ThrfsTer16 pathogenic [+] [+] [–]
30 M-40 positive family history; NS caecum na none PMS2 c.(803+1_804-1)_ (*1_?)del p.? pathogenic [+] [–] [–]
31 F-53 2: 2nd degree caecum + rectum IIIB E PMS2 c.418G>A p.Ser128Leu VUS [+] [+] [–]
32 F-59 3: 1st; 1: 2nd degree rectum IIA E; G; T; L PMS2 c.934A>G p.Met312Val VUS [–] NA [–]
33 F-53 2: 1st; 3: 2nd; 3: 3rd degree sygma in situ L PMS2 c.726G>A p.Gly207Glu VUS [–] NA [–]
34 M-53 2: 1st degree caecum IIIA B CHEK2 c.1100del p.Thr367fs pathogenic [–] NA [–]
35 M-52 positive family history; NS caecum na none CHEK2 c.470T>G p.Ile157Ser likely pathogenic [+] [+] [–]
36 F-51 1: 1st; 1: 2nd; 2: 3rd degree rectum na B; P CHEK2 c.374T>G p.Phe125Cys VUS [–] NA [–]
37 F-59 positive family history; NS sygma IV none CHEK2 c.1313A>G p.Asp438Gly VUS [–] NA [–]
38 M-57 positive family history; NS ascendens IIIB none FANCL c.2T>C p.Met1Thr pathogenic [+] [+] [+]
39 F-43 3: 2nd; 1: 3rd degree transversum IIA G; R FANCL c.1111_1114dup ATTA p.Thr372Asnfs VUS [–] NA [–]
40 M-64 2: 1st degree rectum IIIC none FANCL c. 1111_1114dup ATTA p.Thr372Asnfs VUS [–] NA [–]
41 F-42 1: 1st degree caecum na E; B FANCM c.2953del p.Glu985ArgfsTer3 pathogenic [–] NA [–]
42 M-75 2: 1st; 1: 2nd degree rectum na G FANCM c.643G>A p.Glu215Lys VUS [+] NA [–]
43 F-53 1: 1st; 1: 3rd degree transversum I none BRIP1 c.2392C>T p.Arg798Ter pathogenic [–] NA [–]
44 M-55 1 : 1st; 1: 2nd; 2: 3rd degree ascendens IIIC L BRIP1 c.2392C>T p.Arg798Ter pathogenic [–] NA [–]
45 M-50 1: 1st; 3: 2nd degree rectum IIB E; G ERCC2 c.1403C>T p.Pro468Leu pathogenic [–] NA [–]
46 F-38 1: 1st; 4: 2nd degree ascendens na G; P BLM c.481G>A p.Asp161Asn VUS [–] NA [–]
c.4446_4451dup; p.Glu1482_ likely
47 M-60 2: 1st degree rectum IIA O; P BRCA2; c.545C>T Thr1483dup; pathogenic; [–] NA [–]
BLM AACAGA p.Thr182Ile VUS
48 M-44 1: 1st; 2: 2nd degree transversum IIIB T APC; c.4073C>T; p.Ala1358Val; VUS; VUS [–] NA [–]
PALB2 c.2792T>G p.Leu931Arg
49 M-55 1: 1st; 1: 2nd degree caecum IIIB none KIT; c.1688T>A; p.Ile563Lys; VUS; VUS [–] NA [–]
PALB2 c.2792T>G p.Leu931Arg
50 F-70 2: 1st degree sygma IIB none CDH1 c.1348T>A p.(Tyr450Asn) VUS [–] NA [–]
51 M-59 1: 1st degree ascendens na none CEP57 c.154C>T p.Arg52Cys VUS [–] NA [–]
52 F-50 2: 1st; 1: 2nd degree transversum na B EZH2 c.821G>A p.Arg274Lys VUS [–] NA [–]
53 M-17 1: 2nd degree rectum IIIC R KIT c.2484C>T p.Asn828Asn VUS [–] NA [–]
54 M-49 2: 2nd degree caecum na E unknown [–] [–] [–] [–] NA [–]
55 M-37 positive family history; NS caecum IIB none unknown [–] [–] [–] [+] [+] [–]
56 M-47 2: 1st; 1: 2nd degree caecum IIA none unknown [–] [–] [–] [–] NA [–]
57 M-67 3: 1st; 1: 2nd; 2: 3rd degree caecum IIIB E; B unknown [–] [–] [–] [–] NA [–]
58 F-43 1: 2nd degree transversum na none unknown [–] [–] [–] [–] NA [–]
59 F-30 1: 2nd; 1: 3rd degree rectum IIIC none unknown [–] [–] [–] [–] NA [–]
60 M-49 3: 2nd degree rectum na Br unknown [–] [–] [–] [–] NA [–]
61 F-64 2: 1st; 2: 2nd degree rectum IIB L; B unknown [–] [–] [–] [–] NA [–]
62 F-62 2: 1st; 1: 3rd degree crassl na E unknown [–] [–] [–] [–] NA [–]
63 M-65 1: 1st; 3: 2nd degree rectosygma IIIC E unknown [–] [–] [–] [–] NA [–]
64 F-53 1: 1st degree crassl IV B; E unknown [–] [–] [–] [–] NA [–]
65 F-38 1: 1st degree caecum IIA E unknown [–] [–] [–] [+] [+] [–]
66 F-78 2: 1st degree ascendens

Synchronous: colon + gastric cancer.

 na R; B; Ur unknown [–] [–] [–] [–] NA [–]

Summary of clinical data and molecular defects detected in 41 patients with polyposis syndromes.

n Sex- Age Clinical DX Number of Polyps Type of Polypsa Family History (relatives affected) Extracolonic Cancersb Affected Gene DNA Sequence Change Amino Acid Change ACMG Classification [11]
1 M-40 FAP >100 AD 2: 1st; 1: 2nd; 4: 3rd degree none APC c.-19+2475_*2113+34050del whole gene deletion pathogenic
2 M-38 FAP >100 AD positive NS family history; G APC c.-19+5016_*2113+20168del whole gene deletion pathogenic
3 F-29 FAP >100 AD 2: 1st; 1: 2nd degree none APC c.-19+5016_*2113+20168del whole gene deletion pathogenic
4 F-33 FAP >100 AD 2: 1st; 2: 2nd degree none APC c.-19+2475_*2113+34050del whole gene deletion pathogenic
5 F-29 FAP >100 AD 1: 1st; 1: 2nd degree none APC c.1269G>A p.Trp423Ter pathogenic
6 M-35 FAP >100 AD 1: 1st; 5: 2nd degree none APC c.1660C>T p.Arg554Ter pathogenic
7 M-32 FAP >100 AD 2: 1st degree G APC c.3183_3187del p.Gln1062Terfs pathogenic
8 F-59 FAP >100 AD 1: 1st; 1: 2nd degree none APC c.3183_3187del p.Gln1062Terfs pathogenic
9 M-38 FAP >100 AD 1: 1st; 1: 2nd degree none APC c.3199_3202del p.Ser1068GlyfsTer57 pathogenic
10 M-52 FAP >100 AD no family history none APC c.3404_3405del p.Tyr1135fsTer pathogenic
11 F-38 FAP >100 AD 2: 1st; 1: 3rd degree none APC c.3927_3931del p.Glu1309AspfsTer4 pathogenic
12 M-44 FAP >100 AD 1: 1st degree none APC c.3927_3931del p.Glu1309AspfsTer4 pathogenic
13 F-39 FAP >100 AD no family history none APC c.904C>T p.Arg302Ter pathogenic
BMPR1A; c.-152-2A>G; p.?; pathogenic;
14 M-9 FAP >100 JP 1: 1st degree none KIT c.2484C>T p.Asn828Asn VUS
15 M-47 FAP >100 AD 1: 1st; 3: 3rd degree none FLCN c.1285dupC p.His429ProfsTer27 pathogenic
16 M-38 FAP >100 AD no family history none unknown [–] [–] [–]
17 M-39 oligopolyposis ~30 AD 1: 1st degree none APC c.256A>T p.Lys86Ter pathogenic
18 M-38 oligopolyposis ~10 AD no family history none APC c.3920T>A p.Ile1307Lys pathogenic
19 F-44 oligopolyposis >10 AD/ HP 2: 1st; 4: 2nd degree none BIMPR1A c.1A>G p.Met1Val pathogenic
p.Arg245His/
20 F-40 oligopolyposis ~30 AD no family history none MUTYH c.734G>A/c.734G>A p.Arg245His pathogenic
p.Arg245His/
21 M-47 oligopolyposis ~10 AD 2: 1st degree none MUTYH c.734G>A/c.734G>A p.Arg245His pathogenic
22 M-48 oligopolyposis >10 AD 1: 1st degree none MUTYH c.536A>G/= p.Tyr179Cys/= pathogenic
23 M-55 oligopolyposis >10 AD 1: 1st degree none MUTYH c.536A>G/= p.Tyr179Cys/= pathogenic
24 F-54 oligopolyposis ~50 AD positive family history; NS none MUTYH; FANCL c.536A>G/=; c.2T>C p.Tyr179Cys/=; p.Met1Thr pathogenic
25 M-67 oligopolyposis 50-100 AD 1: 1st degree Pa NTHL1 c.268C>T/c.806G>A p.p.GlnTrp90269Ter/Ter pathogenic
26 F-71 oligopolyposis 7 AD 2: 1st degree E; Pa NTHL1 c.268C>T/= p.Gln90Ter/= pathogenic
27 M-58 oligopolyposis ~10 AD 1: 1st; 2: 3rd degree none NTHL1; c.268C>T/=; p.Gln90Ter/=; VUS
RUNX1 c.711G>C p.Gln237His
28 M-39 oligopolyposis >10 AD 1: 1st degree E BLM c.1642C>T p.Gln548Ter pathogenic
29 F-53 oligopolyposis >10 AD/SE 1: 1st degree B CHEK2 c.902delT p.Leu301TrpfsTer3 pathogenic
30 M-53 oligopolyposis 21 AD no family history none ATM c.2149C>T p.Arg717Trp VUS
31 M-63 oligopolyposis >10 AD no family history none ATM c.9016G>C p.Ala3006Pro VUS
32 F-56 oligopolyposis NA AD 3: 1st degree none MRE11A c.1462C>T p.Arg488Cys VUS
33 M-45 oligopolyposis ~10 AD no family history none MRE11A c.1462C>T p.Arg488Cys VUS
MRE11A; c.1462C>T; p.Arg488Gly; VUS;
34 M-46 oligopolyposis NA no data no family history none BLM; c.3416G>C; p.Arg1139Pro; VUS;
DIS3L2 c.1447C>G p.Arg483Gly VUS
35 M-57 oligopolyposis >10 AD 1: 1st degree none PALB2 c.1846G>C p.Asp616His VUS
36 F-74 oligopolyposis 10 AD 2: 1st degree none POLE c.2527A>G p.Ile843Val VUS
37 M-38 oligopolyposis ~10 AD/ HP 2: 1st; 2: 2nd degree Br; L; P; R FH c.1431_1433dupAAA p.Lys477dup VUS
38 M-54 oligopolyposis >30 AD 1: 1st degree none unknown [–] [–] [–]
39 M-58 oligopolyposis ~10 AD 2: 1st; 7: 2nd degree none unknown [–] [–] [–]
40 M-67 oligopolyposis 20-30 AD 2: 1st degree none unknown [–] [–] [–]
41 F-50 oligopolyposis NA AD 1: 1st degree none unknown [–] [–] [–]
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