Genetic differences in familial adenomatous polyposis syndrome in a Hungarian population: A prospective single center study

Table 1 Clinical characteristics of patients, n (%)

Characteristics of index patients (n = 26)	Number
Gender
Male	7 (26.9)
Female	19 (73.1)
Age at diagnosis (median age)	30.6 (14-61)
Number of polyps
< 100	9 (34.6)
> 100	17 (65.4)
CRC in medical history	7 (26.9)
Extracolonic manifestations
Desmoid cancer	1 (3.8)
Breast cancer	1 (3.8)
Ovarian cancer	1 (3.8)
Testicular cancer	1 (3.8)
Duodenum polyp	4 (15.4)
Gastric polyp	4 (15.4)
Ovarian cyst	2 (7.7)
Indications for surgery
Prophylactic RP-IPAA	12 (46.1)
CRC	6 (23.1)
No surgery	8 (30.8)
CRC in family history	13 (50.0)
Polyposis in family history	20 (76.9)

CRC: Colorectal cancer; RP-IPAA: Restorative proctocolectomy with ileal pouch anal anastomosis.

Table 2 Detected APC germline mutations and other mutations: Adenomatous polyposis coli and other familial adenomatous polyposis-specific gene mutations in this study

APC gene mutations	Patient ID	Transcript number	Exon	Nucleotide changes	Zygosity	Type of mutations	PhyoP100 way score	Phenotypes	Detection method
	1	NM 000038.6		1B region deletion	Heterozygous			FAP	WES
	2	NM 000038.6		1B region deletion	Heterozygous			FAP	WES
	8	NM 000038.6	5	c.505 508del:p.I169fs	Heterozygous	Frameshift		FAP	WES
	9	NM 000038.6			Heterozygous	Genomic deletion		FAP	WES
	10	NM 000038.6			Heterozygous	Genomic deletion		FAP	WES
	11	NM 000038.6			Heterozygous	Genomic deletion		aFAP	WES
	12	NM 000038.6			Heterozygous	Genomic deletion		FAP	WES
	13	NM 000038.6	16	c.3180 3184del:p.Q1062	Heterozygous	Frameshift	0	FAP	WES
	14	NM 000038.6	16	c.C2805A:p.Y935X	Heterozygous	Nonsense	1.441	aFAP	WES
	15	NM 000038.6	10	c.C1248G:p.Y416X	Heterozygous	Nonsense	5.029	FAP	WES
	16	NM 000038.6	16	c.C3340A:p.R1114X	Heterozygous	Nonsense	3.923	FAP	WES
	17	NM 000038.6	16	c.G4057T:p.E1353X	Heterozygous	Nonsense	6.23	FAP	WES
	18	NM 000038.6	14	c.C1660T:p.R554X	Heterozygous	Nonsense	0.753	FAP	WES
	22	NM 000038.6	7	C646-2A>T	Heterozygous	Splice	6.462	FAP	WES
	23	NM 000038.6	5	c.505 508del:pI169fs	Heterozygous	Frameshift	6.5e-06	FAP	WES
	24	NM 000038.6	16	c.C2805A:p.Y935X	Heterozygous	Nonsense	1.441	FAP	WES
Other gene mutation	Patient ID	Transcript number	Exon	Nucleotide changes	Zigosity	Type of mutations	PhyoP100 way score	Phenotypes	Detection method
CHEK2[39]	6	NM 007194.4	4	c.T407C:p.I157T	Heterozygous	Missense	6.65	FAP	WES
MSH3[44,45]	21	NM 002439.5	5	c.998delT:p.Y334Ifs11	Heterozygous	Frameshift	0	aFAP	WES
		NM 002439.5	20	c.G2756A:p.G919D	Heterozygous	Missense	1.000		WES

FAP: Familial adenomatous polyposis; WES: Whole-exon sequencing; aFAP: Attenuated familial adenomatous polyposis.

Table 3 Classification of the detected gene mutations: Classification of patients based on pathogenicity of mutations in genes found

Classification	Identified gene mutations	Transcript number	Zigosity	Frequency of gene mutations (%)	Detection method
	NTHL1[25]	NM 002528.7	Heterozygous	2 (7.69)	WES
Pathogenic	APC	NM 000038.7	Heterozygous	19 (73.08)	WES
	MSH3[44,45]	NM 002439.5	Heterozygous	3 (11.54)	WES
Likely pathogenic	CHEK2[39]	NM 007194.4	Heterozygous	6 (23.08)	WES
	POLE[24,25]	NM 006231.4	Heterozygous	5 (19.23)	WES
	FLCN[47]	NM 144997.7	Heterozygous	1 (3.85)	WES
	PIEZIO1[29,30,44,46]	NM 001142864.4	Heterozygous	4 (15.38)	WES
	ATM[46,48,49]	NM 000051.4	Heterozygous	1 (3.85)	WES
VUS	PMS2[55]	NM 000535.7	Heterozygous	1 (3.85)	WES
	PIK3CA[50,51]	NM 006218.4	Heterozygous	1 (3.85)	WES
	RNF43[52,53]	NM 017763.6	Heterozygous	1 (3.85)	WES
	PDGRA[54]	NM 006206.6	Heterozygous	1 (3.85)	WES
	c.3949G>C.pGlu1317Gln	NM 000038.6	Heterozygous	1 (3.85)	WES

VUS: Variants of unknown significance; WES: Whole-exon sequencing.

Table 4 Correlation between gene mutations and tumor phenotype

Patient ID	Gene mutations	Polyp number	Colectomy	CRC (location)	Age at the diagnosis of CRC	Extracolonic manifestation
1	APC, PIEZO1	> 100	Prophylactic RP-IPAA	Yes (coecum)	24.5	Duodenal and gastric polyp
2	APC, PIEZO1	> 100	Prophylactic RP-IPAA	No		Duodenal and gastric polyp
3	POLE, NTHL1, CHEK2	10-100	Prophylactic RP-IPAA	Yes (coecum, ascending colon)	31	No
4	POLE, NTHL1, PIK3CA, CHEK2	10-100	No	No		No
5	PDGFRA, CHEK2	10-100	No	No		No
6	APC	> 100	Prophylactic RP-IPAA	No		Duodenal and gastric polyp
7	POLE	> 100	Prophylactic RP-IPAA	No		Ovarian tumor
8	APC, FLCN, POLE	> 100	Therapeutic RP-IPAA	Yes (sigmoid colon)	50.5	No
9	APC	> 100	Prophylactic RP-IPAA	No		No
10	APC	> 100	Therapeutic RP-IPAA	Yes (rectum)	49.5	No
11	APC	10-100	No	No		No
12	APC	> 100	Prophylactic RP-IPAA	No		No
13	APC, ATM MSH3	> 100	Prophylactic RP-IPAA	No		No
14	APC	10-100	No	No		No
15	APC	> 100	Prophylactic RP-IPAA	No		No
16	APC, CHEK2, PIEZO1	> 100	Prophylactic RP-IPAA	No		Breast cancer
17	APC	> 100	Prophylactic RP-IPAA	No		No
18	APC, PMS2, CHEK2	> 100	Prophylactic RP-IPAA	No		Duodenal polyp
19	MSH3	10-100	No	No		No
20	APC	10-100	No	No		No
21	MSH3 (pathogenic), MSH3	10-100	Therapeutic RP-IPAA	Yes (rectum)	64	No
22	APC, CHEK2	> 100	Therapeutic RP-IPAA	Yes (sigmoid colon)	31	Testis cancer
23	APC, PIEZO1, POLE, RNF43	> 100	No	No		No
24	APC	> 100	Therapeutic RP-IPAA	Yes (rectum, hepatic flexure)	48	Gastric polyp
25	APC	> 100	Prophylactic RP-IPAA	No		Desmoid tumor
26	APC	10-100	No	No		No

CRC: Colorectal cancer; RP-IPAA: Restorative proctocolectomy with ileal pouch anal anastomosis.

Table 5 Gene variants of unknown significance

Patient ID	VUS genes	Transcript number	Exon	Nucleotide changes	Zigosity	PhyoP100 way score	Detection method
1	PIEZO1	NM 001142864	19	c.G2546A:p.R849H	Heterozygous	1.591	WES
	PIEZO1	NM 001142864	16	c.T2132A:p.M711K	Heterozygous	3.907	WES
2	PIEZO1	NM 001142864	19	c.G2546A:p.R849H	Heterozygous	1.591	WES
	PIEZO1	NM 001142864	16	c.T2132A:p.M711K	Heterozygous	3.907	WES
3	POLE	NM 006231	13	c.C1306T:p.P436S	Heterozygous	9.953	WES
4	POLE	NM 006231	13	c.C1306T:p.P436S	Heterozygous	9.953	WES
	PIK3CA	NM 006218	10	c.A1544G:p.N515S	Heterozygous	4.744	WES
5	PDGFRA	NM 006206.6	22	c.A2897G:p.H966R	Heterozygous	6.868	WES
7	POLE	NM 006231	13	c.C1306T:p.P436S	Heterozygous	9.953	WES
8	FLCN	NM 144997.7	4	c.C115A:p.P39T	Heterozygous	1.645	WES
	POLE	NM 006231	2	c.C154T:p.R52W	Heterozygous	1.914	WES
13	ATM	NM 000051	22	c.G3257A:p.R1086H	Heterozygous	6.258	WES
	MSH3	NM 002439	14	c.C2041T:p.P681S	Heterozygous	5.178	WES
16	PIEZO1	NM 001142864	18	c.G2423A:p.R808Q	Heterozygous	7.747	WES
	PIEZO1	NM 001142864	18	c.G2344A:p.G782S	Heterozygous	3.99	WES
18	PMS2	NM 000535.7	6	c.G682A:p.G228S	Heterozygous	5.643	WES
21	MSH3	NM 002439	20	c.G2756A:p.G919D	Heterozygous	1.000	WES
23	POLE	NM 006231	2	c.C154T:p.R52W	Heterozygous	1.914	WES
	PIEZO1	NM 001142864	31	c.T4252C:p.Y1418H	Heterozygous	4.794	WES
	RNF43	NM 017763	3	c.G319A:p.V107I	Heterozygous	6.609	WES

VUS: Variants of unknown significance; WES: Whole-exon sequencing.