Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score

Figures & data

Table 1 Selected characteristics of the study population, imputed data

Characteristics	Group	Cases (n = 2363)	Controls (n = 2198)	p-valuea
Sex	Female	960 (40.6)	860 (39.1)	0.3013
	Male	1403 (59.4)	1338 (60.9)
Age (years)	<50	115 (4.9)	70 (3.2)	0.0257
	50–59	343 (14.5)	302 (13.7)
	60–69	769 (32.5)	698 (31.8)
	70–79	770 (32.6)	767 (34.9)
	≥80	366 (15.5)	361 (16.4)
Personal history of colonoscopy		521 (22.1)	1208 (55.0)	<0.0001
FH	No FH	1833 (77.6)	1825 (83.0)	<0.0001
	SDR onlyb	214 (9.1)	159 (7.2)
	FDRc	316 (13.4)	214 (9.7)
GRSd	Very low	134 (5.7)	220 (10.0)	<0.0001
	Low	175 (7.4)	220 (10.0)
	Low–medium	383 (16.2)	439 (20.0)
	Medium	431 (18.2)	439 (20.0)
	Medium–high	548 (23.2)	441 (20.0)
	High	300 (12.7)	220 (10.0)
	Very high	392 (16.6)	219 (10.0)
Cancer stage	I	540 (22.8)	–
	II	721 (30.5)	–
	III	750 (31.7)	–
	IV	352 (14.9)	–
Cancer locatione	Proximal colon	765 (32.3)	–
	Distal colon	798 (33.8)	–
	Rectum	800 (33.9)	–

Notes: Values are expressed as n (%).

a p-value for difference in distributions across categories.

b FH in any SDR only.

c FH in at least one FDR.

d Classification of GRS: very low, ≤10th percentile; low, 10th–20th percentile; low–medium, 20th–40th percentile; medium, 40th–60th percentile; medium–high, 60th–80th percentile; high, 80th–90th percentile; very high, >90th percentile.

e Cancers in more than one location were allocated to the most proximal location (n = 34). ‘–’ indicates not applicable.

Abbreviations: FDR, first-degree relative; FH, family history; GRS, genetic risk score; SDR, second-degree relative.

Table 2 Distribution of potential confounders according to FH among controls, imputed data

Characteristics	Group	FH of CRC in FDR,a n = 214 (9.7)	p-value (FH in a FDR vs. no FH)	FH of CRC in SDR,b n = 159 (7.2)	p-value (FH in an SDR vs. no FH)	No FH of CRC,c n = 1825 (83.0)
GRSd	Very low	17 (7.9)	0.8388	18 (11.3)	0.3426	185 (10.1)
	Low	22 (10.3)		10 (6.3)		188 (10.3)
	Low–medium	40 (18.7)		29 (18.2)		370 (20.3)
	Medium	43 (20.1)		34 (21.4)		362 (19.8)
	Medium–high	42 (19.6)		37 (23.3)		362 (19.8)
	High	26 (12.2)		20 (12.6)		174 (9.5)
	Very high	24 (11.2)		11 (6.9)		184 (10.1)
Personal history of colonoscopy		146 (68.2)	<0.0001	90 (56.6)	0.4175	972 (53.3)
Education	≤9 years	135 (63.0)	0.0254	76 (47.8)	0.0031	1114 (61.1)
	10–11 years	27 (12.7)		38 (23.9)		359 (19.7)
	≥12 years	52 (24.3)		45 (28.3)		352 (19.3)
Smoking	Never	114 (53.0)	0.2793	75 (47.2)	0.0890	924 (50.6)
	Formere	85 (39.8)		58 (36.5)		707 (38.8)
	Current	15 (7.2)		26 (16.4)		194 (10.7)
BMI (before diagnosis)	≤18.5 kg/m^2	2 (1.0)	0.6311	– (–)	0.0765	17 (0.9)
	18.5–25 kg/m^2	80 (37.4)		75 (47.0)		680 (37.3)
	25–30 kg/m^2	96 (44.8)		65 (40.9)		877 (48.0)
	>30 kg/m^2	36 (16.9)		19 (12.0)		252 (13.8)
Ever regular use of NSAIDsf		67 (31.5)	0.6708	46 (28.9)	0.2791	601 (32.9)
Ever regular use of HRT (women only)		57 (58.8)	0.0537	34 (52.8)	0.4766	337 (48.3)
Red meat intakeg	<1 per week	34 (15.9)	0.1088	26 (16.4)	0.2703	219 (12.0)
	≥1 per week	131 (61.2)		104 (65.4)		1241 (68.0)
	≥1 per day	49 (22.9)		29 (18.2)		365 (20.0)
Alcohol intakeh	Low risk	164 (76.6)	0.9063	117 (73.6)	0.4460	1392 (76.3)
Physical activityi	≥187.0	102 (47.7)	0.5217	75 (47.2)	0.4970	913 (50.0)
Ever attended regular health checkup		200 (93.4)	0.4310	148 (93.1)	0.5753	1676 (91.8)
Inflammatory bowel diseasesj		2 (0.9)	0.2422	3 (1.9)	0.0103	7 (0.4)

Notes: Values are expressed as n (%).

a FH in at least one FDR.

b FH in any SDR only.

c In any relative (both FDR or SDR).

d Classification of GRS: very low, ≤10th percentile; low, 10th–20th percentile; low–medium, 20th–40th percentile; medium, 40th–60th percentile; medium–high, 60th–80th percentile; high, 80th–90th percentile; very high, >90th percentile.

e Former = stopped smoking more than 2 years ago.

f At least twice weekly for 1 year.

g Consumption of red meat or processed red meat in the previous 12 months.

h Average lifetime daily alcohol consumption, measured in gram ethanol; low-risk alcohol intake defined as drinking less than 12 and 24 g ethanol daily for women and men, respectively.

i Measured in average lifetime MET in the previous 12 months, median in persons without FH = 187.0 MET-hours/week.

j Ulcerative colitis, Crohn’s disease.

Abbreviations: BMI, body mass index; CRC, colorectal cancer; FDR, first-degree relative; FH, family history; GRS, genetic risk score; HRT, hormone replacement therapy; MET, metabolic equivalent of task; NSAIDs, nonsteroidal anti-inflammatory drugs; SDR, second-degree relative.

Table 3 Risk of CRC according to GRS and FH of CRC

Risk factor	Characteristics	Cases, n (%)	Controls, n (%)	OR (95% CI)
				Model 1a	Model 2b	Model 3c
GRSd	Very low	134 (5.7)	220 (10.0)	Ref.	Ref.	Ref.
	Low	175 (7.4)	220 (10.0)	1.31 (0.98–1.75)	1.36 (0.99–1.87)	1.35 (0.98–1.86)
	Low–medium	383 (16.2)	439 (20.0)	1.44 (1.11–1.85)	1.47 (1.12–1.94)	1.48 (1.12–1.95)
	Medium	431 (18.2)	439 (20.0)	1.61 (1.25–2.08)	1.53 (1.17–2.02)	1.51 (1.14–1.98)
	Medium–high	548 (23.2)	441 (20.0)	2.04 (1.59–2.61)	2.09 (1.59–2.73)	2.08 (1.58–2.72)
	High	300 (12.7)	220 (10.0)	2.24 (1.70–2.95)	2.33 (1.72–3.14)	2.32 (1.71–3.13)
	Very high	392 (16.6)	219 (10.0)	2.94 (2.24–3.86)	3.00 (2.24–4.02)	2.96 (2.20–3.97)
FH of CRC	No FH	1833 (77.6)	1825 (83.0)	Ref.	Ref.	Ref.
	SDR only	214 (9.1)	159 (7.2)	1.32 (1.07–1.64)	1.53 (1.21–1.95)	1.53 (1.21–1.95)
	FDR	316 (13.4)	214 (9.7)	1.47 (1.22–1.77)	1.86 (1.52–2.29)	1.83 (1.49–2.25)

Notes: Values are expressed as n (%).

a Adjusted for sex and age.

b Adjusted for sex, age (continuous), education (≤9, 10–11, ≥12 years), previous colonoscopy (yes/no), smoking (current/former/never), HRT among women (yes/no), BMI before diagnosis (weight in kilograms divided by squared height in meters); missing values, n = 75.

c Adjustment like in model 2, plus additional adjustment for FH in analyses for GRS, and additional adjustment for GRS in analyses for FH, respectively; missing values, n = 75.

d GRS with risk alleles as defined in discovery study (Table S1); classification: very low, ≤10th percentile; low, 10th–20th percentile; low–medium, 20th–40th percentile; medium, 40th–60th percentile; medium–high, 60th–80th percentile; high, 80th–90th percentile; very high, >90th percentile.

Abbreviations: BMI, body mass index; CRC, colorectal cancer; FDR, first-degree relative; FH, family history; GRS, genetic risk score; HRT, hormone replacement therapy; OR, odds ratio; Ref., reference; SDR, second-degree relative.

Figure 1 Risk of CRC according to GRS percentiles.

Abbreviations: CRC, colorectal cancer; GRS, genetic risk score; OR, odds ratio.

Figure 2 Dose–response association between the number of risk alleles and risk of CRC, stratified by FH, plotted with a joint reference (no FH, 35 risk alleles).

Abbreviations: CRC, colorectal cancer; FDR, first-degree relative; FH, family history; OR, odds ratio; SDR, second-degree relative.

Table 4 ORs with 95% CI for the risk of CRC according to GRS and having a FH of CRC

GRSa	FH of CRC
	No	SDR only	FDR
Very low	1.00–Ref.	1.56 (0.68–3.57)	1.68 (0.76–3.71)
Low	1.31 (0.92–1.86)	2.69 (1.11–6.52)	2.57 (1.30–5.08)
Low–medium	1.50 (1.10–2.03)	1.94 (1.05–3.59)	2.59 (1.52–4.41)
Medium	1.44 (1.06–1.96)	2.57 (1.48–4.47)	3.27 (1.99–5.37)
Medium–high	2.10 (1.56–2.84)	2.51 (1.46–4.33)	3.95 (2.41–6.46)
High	2.50 (1.78–3.50)	3.38 (1.73–6.60)	2.33 (1.23–4.43)
Very high	2.80 (2.02–3.88)	6.48 (2.93–14.31)	6.14 (3.47–10.84)

Notes: Model adjusted for sex, age, education, previous colonoscopy, smoking, HRT among women, BMI before diagnosis; missing values, n = 75.

a Classification of GRS: very low, ≤10th percentile; low, 10th–20th percentile; low–medium, 20th–40th percentile; medium, 40th–60th percentile; medium–high, 60th–80th percentile; high, 80th–90th percentile; very high, >90th percentile.

Abbreviations: BMI, body mass index; CRC, colorectal cancer; FH, family history; FDR, first-degree relative; GRS, genetic risk score; HRT, hormone replacement therapy; OR, odds ratio; Ref., reference; SDR, second-degree relative.