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

n	Sex- Age	History (relatives affected)	Tumor Location	Stage at D_X	Extracolonic Cancersa	Gene	DNA Sequence Change	Amino Acid Change	ACMG Classification [11]
										MSI Status	MLH1 met	BRAF V600E
1	M-42	1: 1^st; 2: 2^nd degree	transversum	na	G; P; Ur	MLH1	c.896_897insC	p.Pro300SerfsTer7	pathogenic	[+]	[–]	[–]
2	M-55	3: 1^st; 1: 2^nd degree	transversum	na	none	MLH1	c.392C>G	p.Ser131Ter	pathogenic	[+]	[–]	[–]
3	F-49	1: 1^st; 1: 2^nd degree	transversumn	IIA	G; E	MLH1	c.392C>G	p.Ser131Ter	pathogenic	[+]	[–]	[–]
4	M-32	1: 1^st; 2: 2^nd degree	transversum	IIA	none	MLH1	c.392C>G	p.Ser131Ter	pathogenic	[+]	[–]	[–]
5	M-33	1: 1^st; 2: 2^nd 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: 1^st; 3: 2^nd degree	descendens	na	G; P; Ur	MLH1	c.896_897insC	p.Thr372ThrfsTer7	pathogenic	[+]	[–]	[–]
8	F-60	2: 1^st; 2: 2^nd degree	caecum	IIA	none	MLH1	c.392C>G	p.Ser131Ter	pathogenic	[+]	[–]	[–]
9	F-41	1: 1^st; 2: 2^nd degree	caecum	na	E	MLH1	c.1667+1del	p.?	pathogenic	[+]	[–]	[–]
10	F-29	1: 1^st; 2: 2^nd; 2: 3^rd degree	descendens	na	none	MLH1	c.392C>G	p.Ser131Ter	pathogenic	[+]	[–]	[–]
11	F-24	1: 1^st; 1: 2^nd degree	caecum	IIA	E	MLH1	c.244A>G	p.Thr82Ala	likely pathogenic	[+]	[–]	[–]
12	M-40	1: 1^st degree	ascendens	IIA	none	MLH1	c.244A>G	p.Thr82Ala	likely pathogenic	[+]	[–]	[–]
13	M-55	1: 2^nddegree	caecum	IIA	none	MLH1	c.244A>G	p.Thr82Ala	likely pathogenic	[+]	[–]	[–]
14	M-38	2: 1^st; 2: 2^nd; 2: 3^rd degree	ascendens	IIA	P; B	MLH1	c.62C>T	p.Ala21Val	likely pathogenic	[+]	[–]	[–]
15	F-57	1: 1^st; 2: 2^nd degree	ascendens	na	B	MLH1	c.683T>C	p.Leu228Pro	likely pathogenic	[+]	[–]	[–]
16	M-15	1: 1^st; 2: 2^nd degree	transversum	IIA	E	MSH2	c.2211-2A>C	p.?	pathogenic	[+]	[–]	[–]
17	F-41	2: 1^st; 2: 2^nd degree	caecum	IIA	E	MSH2	c.2211-2A>C	p.?	pathogenic	[+]	[–]	[–]
18	M-50	1: 1^st; 2: 2^nd; 2: 3^rd degree	transversum	IIA	E	MSH2	c.2211-2A>C	p.?	pathogenic	[+]	[–]	[–]
19	M-41	3: 2^nd degree	rectosygma	IIIC	E	MSH2	c.209_211+11del	p.?	pathogenic	[+]	[–]	[–]
20	M-46	1: 1^st; 4: 2^nd; 2: 3^rd degree	rectum	na	G	MSH2	c.1786-1788del	p.Asn596del	likely pathogenic	[+]	[–]	[–]
21	F-31	1: 1^st; 2: 2^nd degree	ascendens	IVA	none	MSH6	c.(?_-152)_(260+1_261-1)	p.?	pathogenic	[–]	NA	[–]
22	F-44	1: 1^st; 2: 2^nd degree	rectum	IIIB	E	MSH6	c.458+1G>T	p.?	pathogenic	[–]	NA	[–]
23	F-44	2: 1^st; 2: 2^nd degree	transversum	IIIA	O	MSH6	c.2384T>C	p.Ile795Thr	VUS	[–]	NA	[–]
24	M-81	1: 1^st degree	rectum	IIIC	none	PMS2	gene inversion	–	pathogenic	[–]	NA	[–]
25	M-61	1: 1^st degree	sygma	IIIB	none	PMS2	gene inversion	–	pathogenic	[–]	NA	[–]
26	M-31	1: 1^st degree	caecum	IIA	none	PMS2	c.(803+1_804-1)_ (*1_?)del	p.?	pathogenic	[+]	[–]	[–]
27	M-39	1: 1^st degree	ascendens	IIIC	E	PMS2	c.(803+1_804-1)_ (*1_?)del	p.?	pathogenic	[+]	[–]	[–]
28	M-68	1: 1^st; 1: 2^nd degree	rectosygma + caecum	IIA	none	PMS2	c.2192_2196del	p.Leu731CysfsTer3	pathogenic	[+]	[–]	[–]
29	M-65	1: 1^st 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: 2^nd degree	caecum + rectum	IIIB	E	PMS2	c.418G>A	p.Ser128Leu	VUS	[+]	[+]	[–]
32	F-59	3: 1^st; 1: 2^nd degree	rectum	IIA	E; G; T; L	PMS2	c.934A>G	p.Met312Val	VUS	[–]	NA	[–]
33	F-53	2: 1^st; 3: 2^nd; 3: 3^rd degree	sygma	in situ	L	PMS2	c.726G>A	p.Gly207Glu	VUS	[–]	NA	[–]
34	M-53	2: 1^st 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: 1^st; 1: 2^nd; 2: 3^rd 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: 2^nd; 1: 3^rd degree	transversum	IIA	G; R	FANCL	c.1111_1114dup ATTA	p.Thr372Asnfs	VUS	[–]	NA	[–]
40	M-64	2: 1^st degree	rectum	IIIC	none	FANCL	c. 1111_1114dup ATTA	p.Thr372Asnfs	VUS	[–]	NA	[–]
41	F-42	1: 1^st degree	caecum	na	E; B	FANCM	c.2953del	p.Glu985ArgfsTer3	pathogenic	[–]	NA	[–]
42	M-75	2: 1^st; 1: 2^nd degree	rectum	na	G	FANCM	c.643G>A	p.Glu215Lys	VUS	[+]	NA	[–]
43	F-53	1: 1^st; 1: 3^rd degree	transversum	I	none	BRIP1	c.2392C>T	p.Arg798Ter	pathogenic	[–]	NA	[–]
44	M-55	1 : 1^st; 1: 2^nd; 2: 3^{rd degree}	ascendens	IIIC	L	BRIP1	c.2392C>T	p.Arg798Ter	pathogenic	[–]	NA	[–]
45	M-50	1: 1^st; 3: 2^nd degree	rectum	IIB	E; G	ERCC2	c.1403C>T	p.Pro468Leu	pathogenic	[–]	NA	[–]
46	F-38	1: 1^st; 4: 2^nd degree	ascendens	na	G; P	BLM	c.481G>A	p.Asp161Asn	VUS	[–]	NA	[–]
							c.4446_4451dup;	p.Glu1482_	likely
47	M-60	2: 1^st degree	rectum	IIA	O; P	BRCA2;	c.545C>T	Thr1483dup;	pathogenic;	[–]	NA	[–]
						BLM	AACAGA	p.Thr182Ile	VUS
48	M-44	1: 1^st; 2: 2^nd degree	transversum	IIIB	T	APC;	c.4073C>T;	p.Ala1358Val;	VUS; VUS	[–]	NA	[–]
						PALB2	c.2792T>G	p.Leu931Arg
49	M-55	1: 1^st; 1: 2^nd degree	caecum	IIIB	none	KIT;	c.1688T>A;	p.Ile563Lys;	VUS; VUS	[–]	NA	[–]
						PALB2	c.2792T>G	p.Leu931Arg
50	F-70	2: 1^st degree	sygma	IIB	none	CDH1	c.1348T>A	p.(Tyr450Asn)	VUS	[–]	NA	[–]
51	M-59	1: 1^st degree	ascendens	na	none	CEP57	c.154C>T	p.Arg52Cys	VUS	[–]	NA	[–]
52	F-50	2: 1^st; 1: 2^nd degree	transversum	na	B	EZH2	c.821G>A	p.Arg274Lys	VUS	[–]	NA	[–]
53	M-17	1: 2^nd degree	rectum	IIIC	R	KIT	c.2484C>T	p.Asn828Asn	VUS	[–]	NA	[–]
54	M-49	2: 2^nd degree	caecum	na	E	unknown	[–]	[–]	[–]	[–]	NA	[–]
55	M-37	positive family history; NS	caecum	IIB	none	unknown	[–]	[–]	[–]	[+]	[+]	[–]
56	M-47	2: 1^st; 1: 2^nd degree	caecum	IIA	none	unknown	[–]	[–]	[–]	[–]	NA	[–]
57	M-67	3: 1^st; 1: 2^nd; 2: 3^rd degree	caecum	IIIB	E; B	unknown	[–]	[–]	[–]	[–]	NA	[–]
58	F-43	1: 2^nd degree	transversum	na	none	unknown	[–]	[–]	[–]	[–]	NA	[–]
59	F-30	1: 2^nd; 1: 3^rd degree	rectum	IIIC	none	unknown	[–]	[–]	[–]	[–]	NA	[–]
60	M-49	3: 2^nd degree	rectum	na	Br	unknown	[–]	[–]	[–]	[–]	NA	[–]
61	F-64	2: 1^st; 2: 2^nd degree	rectum	IIB	L; B	unknown	[–]	[–]	[–]	[–]	NA	[–]
62	F-62	2: 1^st; 1: 3^rd degree	crassl	na	E	unknown	[–]	[–]	[–]	[–]	NA	[–]
63	M-65	1: 1^st; 3: 2^nd degree	rectosygma	IIIC	E	unknown	[–]	[–]	[–]	[–]	NA	[–]
64	F-53	1: 1^st degree	crassl	IV	B; E	unknown	[–]	[–]	[–]	[–]	NA	[–]
65	F-38	1: 1^st degree	caecum	IIA	E	unknown	[–]	[–]	[–]	[+]	[+]	[–]
66	F-78	2: 1^st degree	ascendensc	na	R; B; Ur	unknown	[–]	[–]	[–]	[–]	NA	[–]

D_X: diagnosis; ACMG: classification according to the American Collage of Medical Genetics [11]; MSI: microsatellite instability; MLH1 met: methylation of the promoter of the MLH1 gene; BRAF V600E; V600E somatic mutation in the BRAF gene; VUS: variant of unknown significance; NS: not specified; NA: not analyzed.

a 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

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

c Synchronous: colon + gastric cancer.

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).

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 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.

Table 2

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

n	Sex- Age	Clinical D_X	Number of Polyps	Type of Polyps^a	Family History (relatives affected)	Extracolonic Cancers^b	Affected Gene	DNA Sequence Change	Amino Acid Change	ACMG Classification [11]
1	M-40	FAP	>100	AD	2: 1^st; 1: 2^nd; 4: 3^rd 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: 1^st; 1: 2^nd degree	none	APC	c.-19+5016_*2113+20168del	whole gene deletion	pathogenic
4	F-33	FAP	>100	AD	2: 1^st; 2: 2^nd degree	none	APC	c.-19+2475_*2113+34050del	whole gene deletion	pathogenic
5	F-29	FAP	>100	AD	1: 1^st; 1: 2^nd degree	none	APC	c.1269G>A	p.Trp423Ter	pathogenic
6	M-35	FAP	>100	AD	1: 1^st; 5: 2^nd degree	none	APC	c.1660C>T	p.Arg554Ter	pathogenic
7	M-32	FAP	>100	AD	2: 1^st degree	G	APC	c.3183_3187del	p.Gln1062Terfs	pathogenic
8	F-59	FAP	>100	AD	1: 1^st; 1: 2^nd degree	none	APC	c.3183_3187del	p.Gln1062Terfs	pathogenic
9	M-38	FAP	>100	AD	1: 1^st; 1: 2^nd 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: 1^st; 1: 3^rd degree	none	APC	c.3927_3931del	p.Glu1309AspfsTer4	pathogenic
12	M-44	FAP	>100	AD	1: 1^st 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: 1^st degree	none	KIT	c.2484C>T	p.Asn828Asn	VUS
15	M-47	FAP	>100	AD	1: 1^st; 3: 3^rd 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: 1^st 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: 1^st; 4: 2^nd 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: 1^st degree	none	MUTYH	c.734G>A/c.734G>A	p.Arg245His	pathogenic
22	M-48	oligopolyposis	>10	AD	1: 1^st degree	none	MUTYH	c.536A>G/=	p.Tyr179Cys/=	pathogenic
23	M-55	oligopolyposis	>10	AD	1: 1^st 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: 1^st degree	Pa	NTHL1	c.268C>T/c.806G>A	p.p.GlnTrp90269Ter/Ter	pathogenic
26	F-71	oligopolyposis	7	AD	2: 1^st degree	E; Pa	NTHL1	c.268C>T/=	p.Gln90Ter/=	pathogenic
27	M-58	oligopolyposis	~10	AD	1: 1^st; 2: 3^rd degree	none	NTHL1;	c.268C>T/=;	p.Gln90Ter/=;	VUS
							RUNX1	c.711G>C	p.Gln237His
28	M-39	oligopolyposis	>10	AD	1: 1^st degree	E	BLM	c.1642C>T	p.Gln548Ter	pathogenic
29	F-53	oligopolyposis	>10	AD/SE	1: 1^st 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: 1^st 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: 1^st degree	none	PALB2	c.1846G>C	p.Asp616His	VUS
36	F-74	oligopolyposis	10	AD	2: 1^st degree	none	POLE	c.2527A>G	p.Ile843Val	VUS
37	M-38	oligopolyposis	~10	AD/ HP	2: 1^st; 2: 2^nd degree	Br; L; P; R	FH	c.1431_1433dupAAA	p.Lys477dup	VUS
38	M-54	oligopolyposis	>30	AD	1: 1^st degree	none	unknown	[–]	[–]	[–]
39	M-58	oligopolyposis	~10	AD	2: 1^st; 7: 2^nd degree	none	unknown	[–]	[–]	[–]
40	M-67	oligopolyposis	20-30	AD	2: 1^st degree	none	unknown	[–]	[–]	[–]
41	F-50	oligopolyposis	NA	AD	1: 1^st degree	none	unknown	[–]	[–]	[–]

[i] D_X: diagnosis; ACMG: classification according to the American Collage of Medical Genetics [11]; FAP: familial adenomatous polyposis; NA: not available but <100; VUS: variant of unknown significance; [-]: no variant detected.

^a AD: adenomatous; JP: juvenile polyps; HP: hyperplastic; SE: sessile.

^b G: gastric cancer; Pa: pancreatic cancer; E: endometrial cancer; B: breast cancer; Br: brain tumor; L: leukemia; P: prostate cancer; R: renal cancer.

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).

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*).

Articles in this issue

DOI: https://doi.org/10.2478/bjmg-2019-0027 | Journal eISSN: 2199-5761 (formerly 1311-0160) | Journal ISSN: 1311-0160

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Language: English

Page range: 5 - 16

Published on: Dec 21, 2019

Published by: Macedonian Academy of Sciences and Arts

In partnership with: Paradigm Publishing Services

Keywords:

Hereditary colorectal cancer (CRC),

Macedonian population,

mutations

Related subjects:

Medicine,

Basic medical science,

Basic medical science, other

© 2019 M Staninova-Stojovska, N Matevska-Geskovska, M Panovski, B Angelovska, N Mitrevski, M Ristevski, R Jovanovic, AJ Dimovski, published by Macedonian Academy of Sciences and Arts
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Volume 22 (2019): Issue 2 (November 2019)

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

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Table 2

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