Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients

Table 1 41 digestive tract tumour-associated genes

No.	Genes
1	AKT1
2	BRAF
3	CYP2D6
4	GALNT12
5	MET
6	NRAS
7	POLD1
8	SDHC
9	UGT1A1
10	APC
11	BRCA1
12	DPYD
13	GREM1
14	MLH1
15	PDGFRA
16	POLE
17	SDHD
18	ATM
19	BRCA2
20	EGFR
21	HRAS
22	MSH2
23	PIK3CA
24	PTCH1
25	SMAD4
26	BLM
27	CDH1
28	EPCAM
29	KIT
30	MSH6
31	PMS1
32	PTEN
33	STK11
34	BMPRA
35	CHEK2
36	ERBB2
37	KRAS
38	MUTYH
39	PMS2
40	SDHB
41	TP53

Table 2 21 new mutant sites in other genes

Sample	Gene	Description	HGVSc	Mutation type
1	AKT1	p.E135G	c.404A>G	Missense variant
2	APC	p.A41T	c.121G>A	Missense variant
3	APC	p.C417G	c.1249T>G	Missense variant
4	ATM	p.L27501	c.8249T>G	Stop gained
5	ATM	p.A84S	c.250G>T	Missense variant
6	ATM	p.I1332M	c.3996T>G	Missense variant
7	BLM	p.E1035G	c.3104A>G	Missense variant
8	BRCA2	p.D635E	c.1905T>A	Missense variant
9	BRCA2	p.T1346N	c.4037C>A	Missense variant
10	CHEK2	c.908+16T>G	c.908+16T>G	Intron variants
11	CDH1	c.47G>A1	c.47G>A1	3 prime UTR variant
12	CDH1	p.S145Y	c.434C>A	Missense variant
13	CDH1	p.883Yext?1	c.2649G>C	Stop lost
14	GALNT12	c.-6G>T	c.-6G>T	Upstream genetic variant
15	KIT	p.M289I	c.867G>C	Missense variant
16	MLH1	p.T451R	c.1352C>G	Missense variant
17	PMS1	p.D405E	c.1215T>A	Missense variant
18	POLE	p.R1556G	c.4666C>G	Missense variant
19	POLD1	p.K486del	c.1456_1458del	Conservative inframe deletion
20	SDHC	p.L106V	c.316C>G	Missense variant
21	SMAD4	p.A309V	c.926C>T	Missense variant

¹Nonsense mutation leading to protein inactivation.

Table 3 Characterization and pathogenicity of STK11 mutations

Sample	Mutation_type	Description	HGVSc	dbSNP RS	COSM_ID	Classification
1	Stop gained	p.Y601	c.180C>G	/	COSM20874	P
2	Splice acceptor variant	c.921-1G>A	c.921-1G>A	/	COSM49008	LP
3	Splice acceptor variant	c.921-1G>C	c.921-1G>C	rs398123406	/	P
4	Stop gained	p.K841	c.250A>T	rs137853076	COSM3388586; COSM3388585	P
5	Splice acceptor variant	c.921-1G>C	c.921-1G>C	rs398123406	/	P
6	Stop gained	p.Q1231	c.367C>T	/	COSM5224269; COSM380443	P
7	Missense variant	p.W239C	c.717G>T	/	COSM333593; COSM4278104	LP
8	Missense variant	p.R297S	c.891G>T	rs730881984	/	P
9	Stop gained	p.Q1001	c.298C>T	/	/	LP
10	Stop gained	p.K841	c.250A>T	rs137853076	COSM3388586; COSM3388585	P
11	Missense variant	p.R409W	c.1225C>T	rs368466538	COSM25854	VUS
12	Stop gained	p.Q1121	c.334C>T	/	COSM3528680; COSM3528681	LP
13	Missense variant	p.D176N	c.526G>A	rs730881979	COSM4827691; COSM4827690	P
14	Stop gained	p.K841	c.250A>T	rs137853076	COSM3388586; COSM3388585	P
15	Missense variant	p.R304W	c.910C>T	rs786201090	COSM29468	LP
16	Stop gained	p.E1201	c.358G>T	rs775595174	COSM20875	P
17	Stop gained	p.K841	c.250A>T	rs137853076	COSM3388586; COSM3388585	P
18	Conservative inframe deletion	p.Y60fs	c.179dup	rs876661012	COSM5219400; COSM1480565	P
19	Stop gained	p.R861	c.256C>T	/	COSM4767773; COSM4767772	P
20	Stop gained	p.Q1701	c.508C>T	rs121913323	COSM20943	LP
21	Stop gained	p.Q1701	c.508C>T	rs121913323	COSM20943	LP
22	Missense variant	p.S240W	c.719C>G	rs730881976	/	VUS
23	Splice acceptor variant	c.921-2A>G	c.921-2A>G	/	/	LP
24	Splice acceptor variant	c.921-1G>C	c.921-1G>C	rs398123406	/	P
25	Conservative inframe deletion	p.P281fs	c.842del	rs121913321	COSM4336438; COSM20871	P
26	Splice acceptor variant	p.L245F	c.733C>T	/	COSM1523960; COSM4278108	VUS
27	Stop gained	p.Q1371	c.409C>T	rs730881970	COSM48901	P
28	Stop gained	p.Q1371	c.409C>T	rs730881970	COSM48901	P
29	Stop gained	p.Q1231	c.367C>T	/	COSM5224269; COSM380443	P
30	Missense variant	p.D194N	c.580G>A	rs121913315	COSM25847	VUS
31	3_prime_UTR_variant	c.201G>A1	c.201G>A1	rs528679025	/	P
32	Splice acceptor variant	c.598-2A>G	c.598-2A>G	/	/	LP
33	Stop gained	p.Q1591	c.475C>T	/	COSM5002233; COSM27316	LP
34	Gene fusion	STK11-MIDN	/	/	/	LP
35	Conservative inframe deletion	p.D53fs	c.157del	/	COSM27282; COSM6048514	VUS
36	Missense variant	p.D194N	c.580G>A	rs121913315	COSM25847	LP
37	Missense variant	p.P179Q	c.536C>A	/	COSM4822602; COSM4822601	LP
38	Stop gained	p.W3081	c.924G>A	/	/	LP
39	Stop gained	p.E651	c.193G>T	/	COSM20876	P
40	Splice acceptor variant	c.920+1G>C	c.920+1G>C	/	COSM4412472; COSM4412473	LP
41	Conservative inframe deletion	p.C134fs	c.402_403del	rs587782424	COSM5508976; COSM5508975	P
42	Nonsense variant	p.Q220X	c.658C>T	/	COSM13480; COSM4278102	P
43	Nonsense variant	p.Y60X	c.180del	/	COSM20874; COSM27322; COSM48900; COSM5490514	P
44	Missense variant	p.D194N	c.580G>A	rs121913315	/	LP
45	Missense variant	p.R297K	c.890G>A	/	COSM401786; COSM6149636	LP
46	Splice acceptor variant	/	c.863-2A>G	/	/	LP
47	Nonsense variant	p.Q137X	c.409C>T	rs730881970	/	P
48	Splice acceptor variant	c.735-6_735-2del	c.735-6_735-2del	rs759090799	/	VUS
	Conservative inframe deletion2	p.L183fs	c.548del	/	/	LP
49	3 prime UTR variant	c.201G>A1	c.201G>A1	rs528679025	/	LP
	Conservative inframe deletion2	p.C158fs	c.472del	/	/	VUS
50	Stop gained2	p.K811	c.241A>T	/	/	LP
51	Missense variant2	p.R304P	c.911G>C	/	/	P
52	Missense variant2	p.R297K	c.890G>A	/	/	LP
53	Conservative inframe deletion2	p.E145fs	c.426_448del	/	/	LP
54	Stop gained2	p.Y2721	c.816C>A	/	/	LP
55	Stop gained2	p.Q1001	c.298C>T	/	/	LP
56	Conservative inframe deletion2	p.K64fs	c.190_191del	/	/	LP
57	Splice acceptor variant2	c.921-2A>G	c.921-2A>G	/	/	LP
58	Stop gained2	p.Y2921	c.876C>G	/	/	LP
59	Conservative inframe deletion2	p.T212fs	c.634del	/	/	LP
60	Stop gained2	p.K971	c.289A>T	/	/	P
61	Missense variant2	p.H154P	c.461A>C	/	/	VUS
62	Missense variant2	p.A153P	c.457G>C	/	/	VUS
63	Missense variant2	p.L140P	c.419T>C	/	/	VUS
64	Conservative inframe deletion2	p.F264fs	c.792del	/	/	P
65	Stop gained2	p.W3081	c.924G>A	/	/	P
66	Splice acceptor variant2	c.598-2A>G	c.598-2A>G	/	/	LP
67	Conservative inframe deletion2	p.F157fs	c.471_472del	/	/	LP
68	Conservative inframe deletion2	p.S193fs	c.577_578del	/	/	LP
69	Splice acceptor variant2	c.734+1G>A	c.734+1G>A	/	/	LP
70	Missense variant2	p.L290H	c.869T>A	/	COSM20944; COSM25847; COSM4278092	VUS
71	Nonsense variant2	p.Y60X	c.179dup	/	/	P
72	Conservative inframe deletion2	p.L282Afs	c.842dup	/	/	P
73	Conservative inframe deletion2	p.V77Rfs	c.228dup	/	COSM48901	LP

¹Nonsense mutation leading to protein inactivationy.

²The table shows the 26 new STK11 mutation sites.

P: Pathogenic; LP: Likely pathogenic; VUS: Uncertain significance; SNP: Single nucleotide polymorphism.

Table 4 Characterization and pathogenicity of mutations in wild-type Peutz-Jeghers syndrome patients

Sample	Gene	Description	HGVSc	Mutation_type	dbSNP RS	COSM_ID	Classification
1	BLM	p.I947V	c.2839A>G	Missense mutation	rs189925962	NA	VUS
	BMPR1A	p.A13T	c.37G>A	Missense mutation	rs200115604	NA	VUS
	POLD1	p.K486del	c.1456_1458del	Frameshift deletion	NA	NA	VUS
2	CHEK2	p.S252N	c.755G>A	Missense mutation	rs587781379	COSM6004987; COSM6004988	VUS
	MUTYH	c.36+11C>T	c.36+11C>T	Intron mutations	rs2275602	COSN17145138	VUS
	SDHC	p.L106V	c.316C>G	Missense mutation	NA	NA	VUS
3	CHEK2	p.R181H	c.542G>A	Missense mutation	rs121908701	NA	VUS
	MUTYH	c.37_39del1	c.37_39del1	Mutation in the 3' untranslated region	rs373507005	NA	VUS
	MUTYH	c.36+11C>T	c.36+11C>T	Intron mutations	rs2275602	COSN17145138	VUS
	MUTYH	p.G25D	c.74G>A	Missense mutation	rs75321043	NA	VUS
	MUTYH	p.P18L	c.53C>T	Missense mutation	rs79777494	NA	VUS
	POLE	c.3378+10A>G	c.3378+10A>G	Intron mutations	rs193075152	NA	VUS
4	BLM	p.M348I	c.1044G>A	Missense mutation	rs184657475	COSM1580597	VUS
5	BRCA1	p.P1192L	c.3575C>T	Missense mutation	NA	COSM4991001; COSM4991000	VUS
	BRCA2	p.F3328C	c.9983T>G	Missense mutation	rs770826575	NA	VUS
	CHEK2	p.H371Y	c.1111C>T	Missense mutation	rs531398630	COSM4002125	VUS
6	APC	p.I1524R	c.4571T>G	Missense mutation	rs200803739	NA	VUS
7	CDH1	p.S145Y	c.434C>A	Missense mutation	NA	NA	VUS
	POLE	c.3378+10A>G	c.3378+10A>G	Intron mutations	rs193075152	NA	VUS
8	ATM	c.3154-5C>T	c.3154-5C>T	Intron mutations	rs55719759	NA	VUS
	CHEK2	p.S252N	c.755G>A	Missense mutation	rs587781379	COSM6004987; COSM6004988	VUS
	ERBB2	p.V1253M	c.3757G>A	Missense mutation	rs36085723	NA	VUS
9	ATM	p.I1332M	c.3996T>G	Missense mutation	NA	NA	VUS
	POLD1	p.A532T	c.1594G>A	Missense mutation	rs765276497	NA	VUS
10	MUTYH	c.934-2A>G	c.934-2A>G	Splice receptor mutation	rs77542170	NA	VUS
	SMAD4	p.A309V	c.926C>T	Missense mutation	NA	NA	VUS
11	APC	p.A41T	c.121G>A	Missense mutation	NA	NA	VUS
	POLD1	p.R218H	c.653G>A	Missense mutation	rs150010804	NA	VUS
12	SBDS	p.K33R	c.98A>G	Missense mutation	rs373730800	COSM4826086	VUS
13	ATM	p.V519I	c.1555G>A	Missense mutation	NA	NA	VUS
	BRCA2	p.H523R	c.1568A>G	Missense mutation	rs80358443	NA	VUS

¹Nonsense mutation leading to protein inactivation.

P: Pathogenic; LP: Likely pathogenic; VUS: Uncertain significance; NA: Not available.

Table 5 Comparison of clinicopathological parameters between two groups

Project	Wild-type (n = 19)	Mutant-type (n = 73)	P value
Gender
Male	11	44	0.851
Female	8	29
Family history
No	13	51	0.903
Yes	6	22
ABO blood group1
A	7	23	0.964
B	6	21
AB	4	18
O	2	9
Rh blood group1
Negative	0	0
Positive	19	71
Age of initial treatment (years)	18.474 ± 8.8089	12.973 ± 8.3881	0.021
Final age of follow-up (years)	30.842 ± 11.3101	27.425 ± 9.7680	0.239
Total hospitalizations	3 (1, 4)	4 (3, 6)	0.003
Age of first intussusception (years)	22 (14, 27)	15 (9.25, 24)	0.025
Frequency of intussusception	1 (1, 2)	2 (1, 3)	0.006
Age of initial surgery (years)	19 (14, 25)	14 (8, 23.75)	0.007
Number of operations	1 (1, 2)	1 (1, 2)	0.924
Age of mucocutaneous pigmentation appearance (years)	3 (0, 5)	3 (0.5, 5)	0.811
Order of mucocutaneous pigmentation appearance
Lips	2	17	0.213
Lips and limbs	1	46
Lips to limbs	16	10
Time interval from mucocutaneous pigmentation appearance to abdominal symptoms (years)	14.5 (8, 25.5)	10 (5, 15)	0.038
Distribution of gastric polyps
Yes	16 (84.2%)	60 (82.2%)	1
No	3 (15.8%)	13 (17.8%)
Load of gastric polyps	5 (5, 10)	5 (3.25, 10)	0.111
Maximum diameter of gastric polyps (mm)	7 (4.25, 10)	10 (6, 15)	0.012
Distribution of duodenal intestine polyps
Yes	18 (94.7%)	71 (97.3%)	1
No	1 (5.3%)	2 (2.7%)
Load of duodenal intestine polyps	3 (1, 6.5)	7 (4, 15.5)	0.013
Maximum diameter of duodenal intestine polyps (mm)	30 (15, 50)	48 (30, 60)	0.110
Distribution of colorectal polyps
Yes	6 (31.6%)	52 (71.2%)	0.001
No	13 (68.4%)	21 (28.8%)
Load of colorectal polyps	4 (1.5, 12)	3 (1, 10)	0.864
Maximum diameter of colorectal polyps (mm)	30 (15, 50)	25 (13.5, 40)	0.664
Carcinogenesis
Yes	0 (0%)	9 (9.52%)	0.239
No	19 (100%)	64 (90.48%)
Pathology of polyps
Hamartoma	12	35	0.344
Adenoma	2	8
Hamartoma + adenoma	2	4
Carcinogenesis	0	9
Deletion	3	17
Times of endoscopic examinations	2 (1, 2)	2 (2, 4.75)	0.012

¹A few cases did not undergo relevant laboratory tests.

Table 6 Recommended follow-up and intervention strategies for mutant-type and wild-type Peutz-Jeghers syndrome

Age (yr)	Mutant-type		Wild-type
	Surveillance	Intervention	Surveillance	Intervention
< 7	Routine abdominal ultrasound surveillance is recommended every year	Removal of polyps	Abdominal ultrasound is recommended every 3-5 yr	Follow-up observation
8-11	Routine abdominal ultrasound surveillance is recommended every year. For symptomatic individuals with PJS, an abdominal ultrasound should be performed earlier	Removal of polyps	Abdominal ultrasound is recommended every 3-5 yr. For symptomatic individuals with PJS, an abdominal ultrasound should be performed earlier	Removal of polyps
8-18	Total GI surveillance every year (CT scan of small-bowel or enteroscopy/capsule endoscopy should be offered as options	Polyps > 10 mm should be removed	Total GI surveillance 2-3 yr	Removal of polyps
19-30	Routine total GI polyps surveillance every 2-3 yr and screening for systemic tumors	Removal of polyps and treatment of tumors	Routine total GI polyps surveillance every 2-3 yr	Removal of polyps
> 30	Focus on detection of tumors in digestive tract and other organs	Treatment of tumors	Focus on detection of tumors in digestive tract and other organs	Treatment of tumors

PJS: Peutz-Jeghers syndrome; GI: Gastrointestina; CT: Computed tomography.