FGFR genes mutation is an independent prognostic factor and associated with lymph node metastasis in squamous non-small cell lung cancer

Figures & data

Table 1. FGFR mutations identified in 143 patients with squamous lung cell cancer.

Sample	Gene	Exon	Mutations (CDS)^a	Mutations (Amino Acid)^b	Type	Polyphen	SIFT	MAF	Mutated ID^c
1	FGFR1	Exon 5	c.509A > G	E137G (ECD)	SM	PD	Tol	0.26	NA
2	FGFR1	Exon 8	c.842G > C	R250P (ECD)	SM	PD	Dam	0.32	NA
3	FGFR1	Exon 10	c.1200G > T	M369I (ECD)	GM	Benign	Tol	0.58	NA
4	FGFR1	Exon 11	c.1459A > G	M456V (CKD)	SM	Benign	Tol	0.37	NA
5	FGFR1	Exon 13	c.1693A > G	M534V (CKD)	GM	PD	Tol	0.33	NA
6	FGFR1	Exon 19	c.2476G > A	V795I (CKD)	GM	PD	Dam	0.50	NA
7	FGFR2	Exon 7	c.870G > T	W290C (ECD)	SM	PD	Dam	0.25	COSM41286 (5)^f
8	FGFR2	Exon 9	c.1216A > G	K405E (CKD)	GM	Benign	Dam	0.43	NA
9	FGFR2	Exon 11	c.1534G > A	A511T (CKD)	GM	Benign	Tol	0.53	NA
10	FGFR2	Exon 18	c.2390C > A	S796Y (CKD)	SM	PD	Dam	0.50	NA
11	FGFR3	Exon 2	c.87G > C	Q29H (ECD)	GM	PD	Dam	0.52	NA
12	FGFR3	Exon 4	c.403_405delGAA	E135del (ECD)	GM	NA	Dam	0.84	NA
13	FGFR3	Exon 5	c.490C > G	L164V (ECD)	GM	Benign	Tol	0.43	NA
14	FGFR3	Exon 7	c.746C > G	S249C^d (ECD)	SM	PD	Dam	0.34	COSM715 (1312)^f
15	FGFR3	Exon 7	c.746C > G	S249C^d (ECD)	SM	PD	Dam	0.22	COSM715 (1312)^f
16	FGFR3	Exon 11	c.1504G > A	A500T^e (CKD)	SM	Benign	Tol	0.74	COSM88800 (1)
17	FGFR3	Exon 11	c.1504G > A	A500T^e (CKD)	SM	Benign	Tol	0.53	COSM88800 (1)
18	FGFR3	Exon 12	c.1593G > A	M529I (CKD)	GM	PD	Dam	0.38	NA
19	FGFR3	Exon 13	c.1754A > T	K583M (CKD)	GM	PD	Dam	0.52	NA
20	FGFR3	Exon 18	c.2386C > G	L794V (CKD)	GM	PD	Dam	0.48	NA
21	FGFR4	Exon 3	c.146T > A	L49H (ECD)	GM	PD	Dam	0.66	NA
22	FGFR4	Exon 6	c.686C > T	A229V (ECD)	GM	Benign	Tol	0.51	NA
23	FGFR4	Exon 13	c.1727G > A	G576D (CKD)	GM	PD	Tol	0.47	NA
24	FGFR4	Exon 18	c.2266G > T	D756Y (CKD)	SM	PD	Dam	0.87	NA

^a mRNA Reference transcript: FGFR1, NM_001174067.1; FGFR2, NM_022970.3NM_022970; FGFR3, NM_001163213.1; FGFR4, NM_213647.1.

^b Amino acid numbers are derived from the following reference transcripts: FGFR1, NP_001167535; FGFR2, NP_001138387; FGFR3, NP_075254; FGFR4, NP_075252.

^c COSMIC mutation ID indicates that this mutation was included in the COSMIC database, and numbers inside the bracket represent the number of the mutated samples in the COSMIC database.

^d Two samples harbored the FGFR3 somatic mutation S249C.

^e The FGFR3 mutation A500T was detected in paired tumor and adjacent tissues of sample 13 but only in the tumor tissue of sample 14.

^f FGFR2-W290C and FGFR3-S249C were also found in TCGA SQCC samples.

Abbreviations: ECD: extracellular domain; CKD: cytoplasmic domain; SM: somatic mutation (only present in the tumor tissue); GM: germline mutation (present in both tumor and surrounding apparently normal tissue); MAF: mutant allele frequency; PD: Probably damaging; Tol: Tolerate; Dam: Damaging.

Figure 1. Alignment of altered amino acids encoded by the mutations observed in FGFRs.

Somatic mutations are represented by red circles, germline mutations are represented by green circles, and the purple circle indicates the FGFR3-A500 mutation detected in the paired tumor and adjacent tissues of sample 13 but only observed in the tumor tissues of sample 14. Mutations marked with an asterisk are potentially pathogenic sites (predicted as damaging sites by both SIFT and Polyphen2). The vertical axis represents the frequency of the mutation. FGFR2-S290C and FGFR3-S249C are hotspot mutation in squamous lung cancer samples which also be found in TCGA SQCC samples.

Table 2. Clinicopathological features of lung squamous cell carcinoma patients harboring FGFR mutations.

	Total		FGFR somatic mutation (n = 10)			FGFR germline mutation (n = 14)			Any FGFR mutation (n = 24)
	No.	%	No.	%	P	No.	%^b	P	No.	%	P
Age					0.198			0.405			1
≤ 60	56	38.4%	6	10.7%		4	7.1%		10	18%
> 60	84	57.5%	4	4.8%		10	11.9%		14	17%
Gender					0.155			0.423			0.096
Male	120	82.2%	7	5.8%		11	9.2%		18	15%
Female	20	13.7%	3	15.0%		3	2.5%		6	30%
Smoking					0.037			0.423			0.048
Ever	120	82.2%	6	5.0%		11	9.2%		17	14%
Never	20	13.7%	4	20.0%		3	15.0%		7	35%
Stage					0.169			0.208			0.03
I	79	54.1%	3	3.8%		5	6.3%		8	10%
II	38	26.0%	4	10.5%		5	13.2%		9	24%
III	23	15.8%	3	13.0%		4	17.4%		7	30%
Ptrend^a					0.092			0.093			0.013
Differentiation					0.176			1			0.626
Well	4	2.7%	1	25.0%		0	0.0%	0.862	1	25%
Moderate	74	50.7%	6	8.1%		8	10.8%		14	19%
Poor	62	42.5%	3	4.8%		6	9.7%		9	15%
Ptrend^a					0.206			0.918			0.428
Lymph node metastasis					0.052			0.012			0.001
N0	96	65.8%	4	4.2%		5	5.2%		9	9%
N+	44	30.1%	6	13.6%		9	20.5%		15	34%

^a P_trend was derived by logistic regression analyses treating categorical variables as continuous variables.

The bold values indicate that the differences are significant.

Figure 2. FGFR genes mutation status and overall (OS) and disease-free survival (DFS) in SCC patients.

(a)/(c) Patients (10/140) with an FGFR somatic mutation (red curve) had significantly worse DFS and OS compared with patients with no FGFR somatic mutation (green curve). (b)/(d) Patients (24/140) with any FGFR mutation (red curve) had significantly worse OS and FGFR mutations exhibited a trend in OS compared with patients with no FGFR mutation (green curve).

Table

CKD	cytoplasmic domain
DFS	disease-free survival
ECD	extracellular domain
FGFR	fibroblast growth receptor
GM	germline mutation
MAF	mutant allele frequency
NSCLC	non-small cell lung cancer
OS	overall survival
PCR	polymerase chain reaction
SM	somatic mutation
SQCC	squamous cell carcinoma