Association between lung cancer somatic mutations and occupational exposure in never-smokers

Christophe Paris; Pascal Do; Bénédicte Mastroianni; Adrien Dixmier; Patrick Dumont; Eric Pichon; Christos Chouaid; Bruno Coudert; Pascal Foucher; Séverine Fraboulet; Myriam Locatelli-Sanchez; Nathalie Baize; Eric Dansin; Lionel Moreau; Michel Vincent; Pascale Missy; Franck Morin; Denis Moro-Sibilot; Sébastien Couraud

doi:10.1183/13993003.00716-2017

Figures

Tables
Supplementary Materials

Download figure
Open in new tab
Download powerpoint
FIGURE 1
Flow chart of the current analysis.
Download figure
Open in new tab
Download powerpoint
FIGURE 2
Exposure(s) to occupational carcinogens per patient.
Download figure
Open in new tab
Download powerpoint
FIGURE 3
Biomarker mutation frequency in relation to exposure to occupational lung carcinogens: exposure to polycyclic aromatic hydrocarbons (PAH), asbestos, silica, diesel exhaust fumes (DEF), chrome and paints.

TABLE 1

Main demographics, exposure to risk factors, observed mutations, and definite occupational exposure findings in the analysed population

Variable	Included in the current analysis
Subjects n	313
Female sex	260 (83.1)
Age at diagnosis	69.46±11.46
Age <55 years	36 (12)
Age >80 years	50 (16)
BMI
Underweight	14 (4.5)
Normal	164 (53.1)
Pre-obese	91 (29.4)
Obese	40 (12.9)
Education level
High school and higher	139 (44.8)
Secondary school	69 (22.3)
Primary school or no schooling	102 (32.9)
ETS exposure “yes”	206 (66.0)
Cumulative duration of ETS exposure years	30.03±21.09
Family history of lung cancer^#	73 (23.4)
Personal history of cancer^¶	57 (18.2)
Patients exposed to solid fuels from heating or cooking for over 50% of his/her lifetime	62 (25.7)
Personal history of respiratory disease⁺	46 (14.7)
Personal history of respiratory infection^§	103 (32.9)
Histology
Squamous cell carcinoma	22 (7.0)
Adenocarcinoma	273 (87.2)
Other and NOS	18 (5.8)
TTF-1 status by immunohistochemistry
Positive	240 (76.7)
Negative	51 (15.3)
Unknown	25 (8.0)
Mutation results
EGFR	127 (42.8)
KRAS	18 (7.1)
ALK	20 (11.7)
BRAF	10 (5.1)
HER2	8 (4.6)
PIK3	4 (2.5)
TNM 7th edition stage
Stage I	25 (8.1)
Stage II	21 (6.8)
Stage III	36 (11.6)
Stage IV	228 (73.5)
Exposure (definite/probable) to occupational carcinogens
Asbestos	21 (6.7)
PAH	27 (8.6)
Chrome	6 (1.9)
DEF	8 (2.6)
Paint	6 (1.9)
Silica	14 (4.5)
Number of occupational agent exposures per patient
0	273 (87.2)
1	19 (6.1)
2	9 (2.9)
3	4 (1.3)
4	7 (2.2)
5	1 (0.3)

Data are presented as mean±sd or n (%), unless otherwise stated. BMI: body mass index; ETS: environmental tobacco smoke; NOS: not otherwise specified; TTF-1: thyroid transcription factor-1; TNM: tumour, node, metastasis; PAH: polycyclic aromatic hydrocarbons; DEF: diesel exhaust fumes. ^#: two or more relatives affected by lung cancer; ^¶: at least one case of cancer; ⁺: asthma/emphysema/chronic obstructive pulmonary disease/bronchiectasis; ^§: pertussis/tuberculosis/pneumonia.

TABLE 2

Exposure to occupational lung carcinogens and biomarker mutation frequency

		PAH			Asbestos			Silica			DEF			Chrome			Paint
		Unexposed	Exposed	p-value	Unexposed	Exposed	p-value	Unexposed	Exposed	p-value	Unexposed	Exposed	p-value	Unexposed	Exposed	p-value	Unexposed	Exposed	p-value
EGFR^¶	WT	157 (57)	13 (57)	0.942	154 (56)	16 (80)	0.033	161 (57)	9 (69)	0.371	167 (57)	3 (50)	0.703^#	167 (57)	3 (60)	1.0^#	167 (57)	3 (60)	1.0^#
EGFR^¶	Mt	117 (43)	10 (43)	0.942	123 (44)	4 (20)	0.033	123 (43)	4 (31)	0.371	124 (43)	3 (50)	0.703^#	125 (43)	2 (40)	1.0^#	125 (43)	2 (40)	1.0^#
HER2⁺	WT	155 (96)	10 (91)	0.415	1 56 (96)	9 (82)	0.084^#	160 (96)	5 (83)	0.251	162 (95)	3 (100)	1.0^#	163 (96)	2 (67)	0.133^#	164 (95)	1 (100)	1.0^#
HER2⁺	Mt	7 (4)	1 (9)	0.415	6 (4)	2 (18)	0.084^#	7 (4)	1 (17)	0.251	8 (5)	0 (0)	1.0^#	7 (4)	1 (33)	0.133^#	8 (5)	0 (0)	1.0^#
KRAS^§	WT	219 (92)	18 (100)	0.624^#	221 (93)	16 (94)	1.0^#	226 (93)	11 (92)	0.593^#	233 (93)	4 (100)	1.0^#	232 (93)	5 (100)	1.0^#	234 (93)	3 (75)	0.255^#
KRAS^§	Mt	18 (8)	0 (0)	0.624^#	17 (7)	1 (6)	1.0^#	17 (7)	1 (8)	0.593^#	18 (7)	0 (0)	1.0^#	18 (7)	0 (0)	1.0^#	17 (7)	1 (25)	0.255^#
BRAF^ƒ	WT	170 (95)	15 (94)	0.584^#	172 (96)	13 (87)	0.174^#	175 (95)	10 (91)	0.448^#	182 (95)	3 (75)	0.191^#	181 (95)	4 (100)	1.0^#	183 (95)	2 (100)	1.0^#
BRAF^ƒ	Mt	9 (5)	1 (6)	0.584^#	8 (4)	2 (13)	0.174^#	9 (5)	1 (9)	0.448^#	9 (5)	1 (25)	0.191^#	10 (5)	0 (0)	1.0^#	10 (5)	0 (0)	1.0^#
ALK^##	WT	142 (88)	9 (90)	1.0^#	142 (88)	9 (100)	0.601^#	143 (88)	8 (100)	0.598^#	148 (88)	3 (100)	1.0^#	149 (88)	2 (100)	1.0^#	150 (88)	1 (100)	1.0^#
ALK^##	Al	19 (12)	1 (10)	1.0^#	20 (12)	0 (0)	0.601^#	20 (12)	0 (0)	0.598^#	20 (12)	0 (0)	1.0^#	20 (12)	0 (0)	1.0^#	20 (12)	0 (0)	1.0^#
PI3K^¶¶	WT	146 (98)	13 (93)	0.304^#	149 (98)	10 (91)	0.246^#	154 (98)	5 (83)	0.141^#	155 (97)	4 (100)	1.0^#	157 (98)	2 (67)	0.072^#	157 (98)	2 (67)	0.072^#
PI3K^¶¶	Mt	3 (2)	1 (7)	0.304^#	3 (2)	1 (9)	0.246^#	3 (2)	1 (17)	0.141^#	4 (3)	0 (0)	1.0^#	3 (2%)	1 (33)	0.072^#	3 (2%)	1 (33)	0.072^#

Data are presented as n (%), unless otherwise stated. PAH: polycyclic aromatic hydrocarbons; DEF: diesel exhaust fumes; WT: wild type; Mt: mutation; Al: alteration. ^#: two-sided Fisher tests, others are two-sided Chi-squared tests; ^¶: n=297; ⁺: n=173; ^§: n=255; ^ƒ: n=195; ^##: n=171; ^¶¶: n=163.

TABLE 3

Distribution of EGFR mutation type (substitution in exon 21/deletion in exon 19/other or NOS) in relation to occupational exposure

Agent	Exposure	EGFR mutation type				Total
Agent	Exposure	Substitution in Exon 21^#	Deletion in Exon 19^¶	p-value exon 21 versus 19 (Fisher)	Other/NOS	Total
Asbestos	Unexposed	35 (29.7)	72 (61.0)	0.6	11 (9.3)	118 (100)
Asbestos	Exposed	2 (50.0)	2 (50.0)	0.6	0 (0.0)	4 (100)
PAH	Unexposed	33 (29.2)	70 (61.9)	0.437	10 (8.8)	113 (100)
PAH	Exposed	4 (44.4)	4 (44.4)	0.437	1 (11.1)	9 (100)
Chrome	Unexposed	36 (30.0)	74 (61.7)	0.333	10 (8.3)	120 (100)
Chrome	Exposed	1 (50.0)	0 (0.0)	0.333	1 (50.0)	2 (100)
Diesel	Unexposed	36 (30.3)	72 (60.5)	1.0	11 (9.2)	119 (100)
Diesel	Exposed	1 (33.3)	2 (66.7)	1.0	0 (0.0)	3 (100)
Paints	Unexposed	35 (29.2)	74 (61.7)	0.109	11 (9.2)	120 (100)
Paints	Exposed	2 (100.0)	0 (0.0)	0.109	0 (0.0)	2 (100)
Silica	Unexposed	36 (30.5)	72 (61.0)	1.0	10 (8.5)	118 (100)
Silica	Exposed	1 (25.0)	2 (50.0)	1.0	1 (25.0)	4 (100)

Data are presented as n (%), unless otherwise stated. NOS: not otherwise specified; PAH: polycyclic aromatic hydrocarbons. ^#: L858R/L861Q/P848L/Exon 21 subst. NOS; ^¶: Del 19/Exon 19 NOS.

TABLE 4

Binary logistic regression analysis in univariate and adjusted models for biomarker mutation occurrence in relation to occupational exposure (binary variable)^#

Biomarker	Occupational exposure	Crude OR	(95% CI)	p-value	AOR^¶	(Lower 95% CI)	p-value
EGFR	PAH	1.032	(0.437–2.436)	0.942	1.340	(0.533–3.369)	0.533
	Asbestos	0.313	(0.102–0.960)	0.042	0.376	(0.118–1.201)	0.099
	Silica	0.582	(0.175–1.933)	0.377	0.703	(0.197–2.515)	0.588
	DEF	1.347	(0.267–6.786)	0.718	2.541	(0.392–16.463)	0.328
	Chrome	0.891	(0.147–5.411)	0.900	1.011	(0.156–6.536)	0.991
	Paint	0.891	(0.147–5.411)	0.900	0.875	(0.141–5.421)	0.886
HER2	PAH	2.214	(0.248–19.799)	0.477	1.644	(0.153–17.656)	0.681
	Asbestos	5.778	(1.019–32.775)	0.048	5.089	(0.732–35.395)	0.100
	Silica	4.571	(0.469–44.538)	0.191	3.297	(0.239–45.395)	0.373
	Chrome	11.643	(0.940–144.249)	0.056	7.779	(0.488–124.078)	0.147
KRAS	Asbestos	0.813	(0.102–6.501)	0.845	0.867	(0.102–7.354)	0.896
	Silica	1.209	(0.147–9.925)	0.860	1.363	(0.144–12.871)	0.787
	Paint	4.588	(0.453–46.507)	0.197	5.072	(0.452–56.942)	0.188
BRAF	PAH	1.259	(0.149–10.622)	0.832	1.136	(0.116–11.116)	0.913
	Asbestos	3.308	(0.636–17.203)	0.155	3.411	(0.565–20.595)	0.181
	Silica	1.944	(0.224–16.895)	0.547	1.697	(0.153–18.855)	0.667
	DEF	6.741	(0.636–71.395)	0.113	11.103	(0.507–243.270)	0.126
ALK	PAH	0.830	(0.100–6.923)	0.864	NC

AOR: adjusted odds ratio; PAH: polycyclic aromatic hydrocarbons; DEF: diesel exhaust fumes; NC: not computable. ^#: for all categories, the unexposed patient group is the reference (not shown). ^¶: adjusted for sex (binary), age at diagnosis (continuous), cumulative duration (years) of passive smoking exposure (continuous) and body mass index (continuous). Others are not computable.