Novel CDH1 germline mutations identified in Chinese gastric cancer patients

Table 1 Frequency distributions of variables in gastric cancer cases and controls n (%)

Variables	Cases	Controls	P value
Number	236	240
Age (yr)			0.997
≤ 49	19 (8.1)	19 (7.9)
50-59	65 (27.5)	65 (27.1)
60-69	94 (39.8)	98 (40.8)
≥ 70	58 (24.6)	58 (24.2)
Gender			0.915
Male	178 (75.4)	180 (75.0)
Female	58 (24.6)	60 (25.0)
Family history
Familial recurrence for gastric cancer1	6 (2.5)
Low familial recurrence for gastric cancer2	39 (16.5)
Young age (< 50 yr) of sporadic disease	16 (6.8)
Old age (≥ 50 yr) of sporadic disease	175 (74.2)
Histologic grade3
Poorly differentiated adenocarcinoma	64 (39.5)
Moderately differentiated adenocarcinoma	69 (42.6)
Well differentiated adenocarcinoma	29 (17.9)
Depth invasion (pT)34
pT1	12 (7.4)
pT2	32 (19.8)
pT3	109 (67.3)
pT4	9 (5.5)
Lymph node involvement (pN)34
pN0	35 (21.6)
pN1	3 (1.9)
pN2	65 (40.1)
pN3	59 (36.4)
Distant metastasis (M)34
M0	161 (99.4)
M1	1 (0.6)
TNM stage34
Stage I	8 (4.9)
Stage II	39 (24.1)
Stage III	115 (71.0)

¹Individuals with gastric cancer and two or more first-degree relatives with gastric cancer or related cancers;

²Individuals with gastric cancer and one first-degree relative with gastric cancer or related cancers;

³Available for 162 cases;

⁴According to the National Comprehensive Cancer Network guidelines on tumor-node-metastasis (TNM) Staging Classification for Carcinoma of the Stomach (7^th ed., 2010) by the American Joint Committee on cancer.

Table 2 Novel CDH1 mutations and polymorphism identified in Chinese gastric cancer patients n (%)

Gene location	Sequence variant	Consequence	Genotype
			Gastric cancer patients (n = 236)	Control (n = 240)	P value
5’UTR	c.-49 G>T	Substitution at the 5’UTR	4 (1.7)	3 (1.3)	0.723
Exon 1	c.44_46delTGC	Loss of the 15th code (Leu)	2 (0.85)	0 (0.0)	0.245
Exon 5	c.604G>A	Missense V202I	1 (0.4)	0 (0.0)	0.496
Intron 9	c.1320+7 A>G	Substitution of invariant A	1 (0.4)	0 (0.0)	0.496

Two-sided χ² test or Fisher's exact test for genotype distribution

Table 3 Polymorphisms identified in CDH1 in Chinese gastric cancer patients and controls

Gene location	Sequence variant	Condon	MAF in 236 GC patients	MAF in 240 controls	Reported MAF1
Promoter	-164del T(g.4837delT)	-	0.004del T	0.000del T	rs5030658: NA
Promoter	-161C>A(g.4840C>A)	-	0.242A	0.227A	rs16260: 0.227A
Promoter	-73A>C (g.4928A>C)	-	0.129C	0.146C	rs28372783: 0.040C
Intron 1	c.48+6C>T	-	0.280C	0.271C	rs3743674: 0.214C
Intron1	c.48+62_48+63delinsCGTGCCCCAGCCC	-	0.280del2	0.271del2	rs3833051: NA
Exon 7	c.894C>T	A298A	0.002T	0.000T	rs139110184: NA
Exon 9	c.1224G>A	A408A	0.002A	0.000A	rs200161607: 0.001A
Exon 12	c.1888C>G	L630V	0.004G	0.004G	rs2276331: 0.002G
Exon 13	c.2076T>C	A692A	0.377T	0.404T	rs1801552: 0.307T
Exon 14	c.2253C>T	N751N	0.089T	0.102T	rs33964119: 0.058T

¹From http://www.ncbi.nlm.nih.gov/projects/SNP/;

²Coincident with MAF of c.48+6C>T variant. GC: Gastric cancer; MAF: Minor allele count; NA: Not available.

Table 4 Available clinical-pathologic characteristics of the gastric cancer cases with novel CDH1 mutations

ID code	Age onset (yr)	Gender	Family history	Histologic grade	Depth invasion (pT)	Lymph node involvement (pN)	Distant metastasis (M)	CDH1 variants
G45	66	Female	Sporadic	Poorly differentiated adenocarcinoma	pT3	pN3	M0	c.44_46delTGC
G68	51	Male	Sporadic	NA	NA	NA	NA	c.44_46delTGC
G1501	58	Male	Sporadic	Moderately differentiated adenocarcinoma	pT2	pN3	M0	c.604G>A (V202I)
G26	56	Male	Sporadic	Moderately differentiated adenocarcinoma	pT3	pN2	M0	c.1320+7 A>G

¹Also harbors the MLH1 c.2101C>A (Q701K) mutation[16]. NA: Not available.

Table 5 CDH1 missense mutations analyzed by sorting intolerant from tolerant and PolyPhen

Sequence variant	Structural alteration	SIFT scores	PSIC score difference	Prediction
c.604G>A	V202I	0.20	0.381	Benign
c.1888C>G	L630V	0.02	1.748	Probably damaging

SIFT: Sorting intolerant from tolerant; PSIC: Position-specific independent counts.