MC1R variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project

Figures & data

Table 1 Description of the studies included in the analysis

Study	Country	Cases	Controls	Control typea	RH phenotypeb in controls	Available confoundersc
Kennedy et al^Citation39	The Netherlands	115	377	Hospital	210 (56%)	Sun exposure, sunburn, common and atypical nevi
Landi et al^Citation34	Italy	163	169	Healthy	83 (49%)	Sun exposure, sunburn, common nevi
Bishop et al^Citation40	UK	1567	469	Hospital	314 (67%)	Sunburnd
Kanetsky et al^Citation18	USA	766	322	Healthy	262 (81%)	Sun exposure, sunburn, atypical nevie
Menin et al^Citation41,f	Italy	118	168	Healthy	70 (42%)	Sunburn, common and atypical nevi
Ghiorzo et al^Citation42	Italy	236	355	Healthy	224 (63%)	Sunburnd
Penn et al^Citation30	USA	865	759	Healthy	339 (45%)	Sun exposure, sunburn, common nevi
Total		3,830	2,619		1,502 (57%)

Notes:

a Healthy controls were population controls, friends or partners of cases, outpatients, or hospital personnel.

b Defined as presence of red hair, freckles, or skin type I/II;

c Beyond age and sex, which were available in all seven studies. Confounders with more than 20% of missing data not listed. Sun exposure includes separate information on chronic and intermittent sun exposure.

d Information on atypical nevi was also available, but with more than 20% of subjects with missing data.

e Not included in risk model analysis because of missing data on common nevi.

f Included an unpublished group of sporadic melanoma cases that were included in the present analysis. Study approach, control group, and genetic analysis were the same as described in Menin et al.⁴¹

Abbreviation: RH, red hair.

Figure 1 Forest plot for NDE, NIE, and TE of any MC1R variant on melanoma risk.

Notes: CDE estimates the direct effect of MC1R on melanoma when the mediator is controlled at level 0 (absent) or 1 (present) uniformly in the population, NDE essentially averages CDE over the population, NIE estimates the indirect effect of MC1R mediated by RH phenotype, and TE is the overall melanoma risk estimate for MC1R carriers and in each study is the product of NDE and NIE.

Abbreviations: CDE, control direct effect; NDE, natural direct effect; NIE, natural indirect effect; PY, publication year; RH, red hair; SOR, summary OR; TE, total effect.

Figure 2 Forest plot for control direct effect of any MC1R variant on melanoma risk according to RH phenotype.*

Notes: *Defined as presence of red hair, freckles, or skin type I/II. Control direct effect estimates the direct effect of MC1R on melanoma when the mediator is controlled at level 0 (absent) or 1 (present) uniformly in the population.

Abbreviations: PY, publication year; RH, red hair; SOR, summary OR.

Table 2 ORs with 95% CIs for melanoma risk according to a base clinical model and the same model with inclusion of MC1R variants

	All participants (n=4,390)		RH participants (n=2,654)		Non-RH participants (n=1,736)
	Base model	Base model + MC1R	Base model	Base model + MC1R	Base model	Base model + MC1R
Agea	0.97 (0.94–1.00)	0.97 (0.94–1.00)	0.96 (0.92–0.99)	0.96 (0.92–0.99)	0.99 (0.94–1.04)	0.99 (0.94–1.04)
Sex
Male	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)
Female	1.01 (0.89–1.16)	1.03 (0.91–1.18)	0.92 (0.77–1.09)	0.92 (0.77–1.10)	1.18 (0.96–1.45)	1.23 (1.00–1.52)
Sunburn
None	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)
Any	1.15 (0.98–1.35)	1.11 (0.94–1.30)	1.16 (0.94–1.43)	1.13 (0.91–1.39)	1.13 (0.88–1.47)	1.08 (0.84–1.41)
Common nevi
≤30	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)	1.00 (reference)
>30	3.37 (2.90–3.92)	3.40 (2.92–3.96)	3.46 (2.86–4.18)	3.47 (2.87–4.20)	3.25 (2.53–4.16)	3.30 (2.57–4.24)
Phenotype
Non-RH	1.00 (reference)	1.00 (reference)	–	–	–	–
RH	1.64 (1.43–1.88)	1.52 (1.32–1.75)	–	–	–	–
MC1R
None	–	1.00 (reference)	–	1.00 (reference)	–	1.00 (reference)
Any variant	–	1.63 (1.40–1.90)	–	1.55 (1.25–1.92)	–	1.76 (1.41–2.19)
Only r variants	–	1.24 (1.04–1.47)	–	1.07 (0.84–1.37)	–	1.45 (1.14–1.86)
≥1 R variant	–	2.08 (1.76–2.46)	–	1.92 (1.53–2.41)	–	2.25 (1.73–2.92)

Notes:

a Per 5-year increase. Significant ORs are in bold. All models are adjusted for variables included in the table + study center. Two separate models were created for 1) any MC1R variant vs wild type and 2) only r variants and ≥1R variant vs wild type. R and r alleles were defined basing on their stronger or weaker association with the RH phenotype for the most common variants^44,67–70 and on likely pathogenicity using the algorithm proposed by Davies et al³² for the less common variants.

Abbreviation: RH, red hair.

Figure 3 ROC curve comparison between base clinical model and the same model with inclusion of MC1R variants for patients with no RH phenotype.*

Notes: (A) MC1R defined as the presence or absence of any MC1R variant and (B) as no MC1R variant, only r variants, and ≥1 R variants. *Non-RH patients defined as those without RH and freckles and with skin type III/IV. R and r alleles were respectively defined basing on their stronger or weaker association with the RH phenotype for the most common variants^44,67–70 and on likely pathogenicity using the algorithm proposed by Davies et al³² for the less common variants.

Abbreviations: RH, red hair; ROC, receiver-operating characteristic.

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