eTable1. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pigmentary traits and measures of residential UV exposure at inclusion in relation to differentiated thyroid cancer risk. E3N Cohort, 1990-2008 (n=86,960)

(1)

eTable1. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pigmentary traits and measures of residential UV exposure at inclusion in relation to differentiated thyroid cancer risk. E3N Cohort, 1990-2008 (n=86,960)

Model 1

^a

Model 2

^b

Model 3

^c

Cases

HR 95% CI HR 95% CI HR 95% CI

Number of nevi

None 23 ref - ref - ref -

Few 117 1.3 [0.8-2.0] 1.3 [0.8-2.0] 1.3 [0.8-2.0]

Many 171 1.6 [1.0-2.5] 1.6 [1.0-2.4] 1.5 [1.0-2.4]

Very many 49 1.8 [1.1-3.0] 1.7 [1.0-2.8] 1.6 [1.0-2.7]

P for linear trend 0.004 0.01 0.03

Number of freckles

None 131 ref - ref - ref -

Few 79 1.0 [0.7-1.3] 1.0 [0.7-1.3] 1.0 [0.7-1.3]

Many 125 1.3 [1.0-1.6] 1.2 [1.0-1.6] 1.2 [0.9-1.5]

Very many 25 1.4 [0.9-2.2] 1.4 [0.9-2.2] 1.3 [0.8-2.1]

Hair color

Red 7 1.1 [0.5-2.3] 1.0 [0.5-2.2] 0.9 [0.4-2.0]

Blond 35 0.9 [0.6-1.3] 0.9 [0.6-1.3] 0.9 [0.6-1.3]

Chestnut 227 ref - ref - ref -

Brown/Dark 91 0.8 [0.6-1.1] 0.8 [0.6-1.1] 0.8 [0.6-1.1]

Skin complexion

Very fair 6 1.5 [0.6-3.3] 1.3 [0.6-3.0] 1.1 [0.5-2.6]

Fair 211 1.1 [0.9-1.3] 1.0 [0.8-1.3] 0.9 [0.7-1.2]

Medium 137 ref - ref - ref -

Dark/Very dark 6 1.2 [0.5-2.6] 1.2 [0.5-2.6] 1.2 [0.5-2.8]

(2)

Skin sensitivity to sun exposure

Not sensitive 74 ref - ref - ref -

Moderately sensitive 169 1.1 [0.8-1.4] 1.1 [0.8-1.4] 1.0 [0.8-1.4]

Highly sensitive 117 1.2 [0.9-1.6] 1.2 [0.9-1.6] 1.1 [0.8-1.6]

Mean annual daily ambient total UV level

(J/m²)

< 624,420 70 ref - ref - ref -

624,420 – 667,469 80 1.1 [0.8-1.6] 1.1 [0.8-1.6] 1.1 [0.8-1.6]

667,470 – 763,799 104 1.5 [1.1-2.0] 1.5 [1.1-2.0] 1.5 [1.1-2.0]

≥ 763,800 106 1.5 [1.1-2.1] 1.5 [1.1-2.0] 1.5 [1.1-2.0]

Mean spring/summer daily ambient total UV level

(J/m²)

< 976,920 71 ref - ref - ref -

976,920 – 1,032,839 74 1.0 [0.7-1.4] 1.0 [0.7-1.4] 1.0 [0.7-1.4]

1,032,840 – 1 ,146,359 111 1.6 [1.1-2.1] 1.5 [1.1-2.1] 1.5 [1.1-2.1]

≥ 1,146,360 104 1.5 [1.1-2.0] 1.4 [1.0-1.9] 1.4 [1.0-1.9]

Mean autumn/winter daily ambient total UV level

(J/m²)

<272,880 74 ref - ref - ref -

272,880-302,279 76 1.0 [0.7-1.4] 1.0 [0.7-1.4] 1.0 [0.7-1.4]

302,280-382,739 106 1.4 [1.0-1.9] 1.4 [1.0-1.9] 1.4 [1.0-1.9]

≥ 382,740 104 1.4 [1.0-1.9] 1.4 [1.0-1.8] 1.4 [1.0-1.8]

Mean annual daily ambient UVB level

(J/m²)

< 21,360 52 ref - ref - ref -

21,360 – 22,499 99 1.8 [1.3-2.5] 1.8 [1.3-2.5] 1.8 [1.3-2.5]

22,500 – 26,519 109 2.0 [1.5-2.8] 2.0 [1.5-2.8] 2.0 [1.5-2.8]

≥ 26,520 100 1.9 [1.3-2.6] 1.8 [1.3-2.5] 1.8 [1.3-2.6]

Mean spring/summer daily ambient UVB level

(J/m²)

< 36,060 50 ref - ref - ref -

(3)

36,060 – 37,859 97 1. 8 [1.3-2.5] 1.8 [1.3-2.5] 1.8 [1.3-2.5]

37,860 – 43,979 110 2.1 [1.5-2.9] 2.1 [1.5-2.9] 2.1 [1.5-3.0]

≥ 43,980 103 2.0 [1.4-2.8] 1.9 [1.4-2.7] 1.9 [1.4-2.7]

Mean autumn/winter daily ambient UVB level

(J/m²)

<6660 57 ref - ref - ref -

6660-7439 94 1.4 [1.0-1.9] 1.4 [1.0-1.9] 1.4 [1.0-1.9]

7440-9659 108 1.7 [1.2-2.4] 1.7 [1.2-2.4] 1.7 [1.2-2.4]

≥ 9660 101 1.6 [1.2-2.2] 1.6 [1.1-2.2] 1.6 [1.1-2.2]

Mean annual ambient UVA level (

J/m²)

< 603,240 71 ref - ref - ref -

603,240 – 644,499 79 1.1 [0.8-1.5] 1.1 [0.8-1.5] 1.1 [0.8-1.5]

644,500– 737,279 105 1.5 [1.1-2.0] 1.5 [1.1-2.0] 1.5 [1.1-2.0]

≥ 737,280 105 1.5 [1.1-2.0] 1.5 [1.1-2.0] 1.5 [1.1-2.0]

Mean Autumn/Winter ambient UVA level (

J/m²)

<266,280 74 ref - ref - ref -

266,280-294,839 77 1.0 [0.8-1.4] 1.1 [0.8-1.4] 1.1 [0.8-1.4]

294,840-373,079 105 1.4 [1.0-1.9] 1.4 [1.0-1.9] 1.4 [1.0-1.9]

≥ 373,080 104 1.4 [1.1-1.9] 1.4 [1.0-1.8] 1.4 [1.0-1.9]

Mean spring/summer ambient UVA level (

J/m²)

< 940,800 71 ref - ref - ref -

940,800 – 995,159 74 1.0 [0.7-1.4] 1.0 [0.7-1.4] 1.0 [0.7-1.4]

995,160 – 1,103,579 111 1.6 [1.2-2.1] 1.6 [1.2-2.1] 1.6 [1.2-2.1]

≥ 1,103,580 104 1.5 [1.1-2.0] 1.4 [1.1-1.9] 1.4 [1.1-1.9]

Latitude

< 45.09 102 ref - ref - ref -

45.09 – 47.35 105 1.0 [0.8-1.3] 1.0 [0.8-1.4] 1.0 [0.8-1.4]

(4)

47.36 – 48.50 81 0.9 [0.6-1.1] 0.9 [0.6-1.1] 0.8 [0.6-1.1]

≥ 48.51 72 0.7 [0.5-0.9] 0.7 [0.5-0.9] 0.7 [0.5-0.9]

Longitude

< 1.23 95 ref - ref - ref -

1.23 – 2.27 99 1.1 [0.8-1.4] 1.0 [0.8-1.4] 1.0 [0.8-1.4]

2.28 – 4.49 77 0.8 [0.6-1.1] 0.8 [0.6-1.1] 0.8 [0.6-1.1]

≥ 4.50 89 0.9 [0.7-1.2] 0.9 [0.7-1.2] 0.9 [0.7-1.2]

UV: ultraviolet

a Adjusted for age, further stratified by year of birth (1925-1929, 1930-1934, 1935-1939, 1940-1944, 1945-1950)

b further adjusted for smoking status (never, current, past), personal history of dysthyroidism (yes, no), personal history of goiter or nodules (yes, no), and tertiles of body mass index (≤22, 23-24, or ≥24 kg/m²).

cfurther adjusted for pigmentary traits and, for pigmentary traits, mean spring/summer ambient UVB level

(5)

eTable2: Hazard Ratios (HRs) and 95% confidence intervals (CIs) for pigmentary traits and latitude, longitude and residential spring/summer UVB exposure at inclusion in relation to risk of micro- and macro-cancers. E3N Cohort, 1990-2008 (n=86,960)

Micro-cancers Macro-cancers

Cases

(n=146) HR^a 95% CI Cases

(n=207) HR^a 95% CI Number of nevi

None 10 ref - 12 ref -

Few 46 1.2 [0.6-2.3] 70 1.5 [0.8-2.8]

Many 71 1.5 [0.7-2.8] 96 1.7 [0.9-3.0]

Very many 19 1.5 [0.7-3.2] 29 1.9 [0.9-3.7]

p for linear trend 0.15 0.08

Number of freckles

Few 37 1.1 [0.7-1.7] 40 0.8 [0.5-1.2]

Many 44 1.1 [0.7-1.6] 77 1.2 [0.9-1.7]

Very many 10 1.4 [0.7-2.8] 14 1.2 [0.7-2.2]

Hair color

Red 3 1.1 [0.3-3.6] 4 0.9 [0.3-2.5]

Blond 15 1.0 [0.6-1.8] 19 0.8 [0.5-1.3]

Chestnut 94 ref - 129 ref -

Brown/Dark 34 0.6 [0.4-0.9] 55 1.0 [0.7-1.3]

Skin complexion

Very fair 2 0.6 [0.1-2.8] 4 1.6 [0.6-4.7]

Fair 75 0.6 [0.4-0.9] 130 1.2 [0.8-1.7]

Medium 63 ref - 73 ref -

Dark/Very dark 6 3.1 [1.3-7.4] 0 - -

(6)

Skin sensitivity to sun exposure

Not sensitive 33 ref - 40 ref -

Moderately sensitive 66 1.1 [0.7-1.7] 99 1.0 [0.7-1.5]

Highly sensitive 47 1.3 [0.8-2.2] 68 1.0 [0.6-1.6]

Mean spring/summer daily ambient UVB level (J/m²)

< 36,060 22 ref - 27 ref -

36,060 – 37,859 36 1.5 [0.9-2.6] 59 2.0 [1.3-3.2]

37,860 – 43,979 53 2.3 [1.4-3.8] 54 1.9 [1.2-3.1]

≥ 43,980 35 1.4 [0.8-2.4] 67 2.4 [1.5-3.8]

Latitude

< 45.09 42 ref - 60 ref -

45.09– 47.35 43 1.1 [0.7-1.6] 58 1.0 [0.7-1.4]

47.36 – 48.50 34 0.9 [0.6-1.4] 46 0.8 [0.5-1.2]

≥ 48.51 27 0.7 [0.4-1.1] 43 0.7 [0.5-1.0]

Longitude

< 1.23 44 ref - 48 ref -

1.23 – 2.27 41 0.9 [0.6-1.4] 56 1.2 [0.8-1.7]

2.28 – 4.4 28 0.6 [0.4-1.0] 47 0.9 [0.6-1.4]

≥ 4.5 33 0.7 [0.4-1.1] 56 1.1 [0.8-1.7]

UVB: ultraviolet B

a Adjusted for age, smoking status (ever, current, past), personal history of dysthyroidism (yes, no), personal history of goiter or nodules (yes, no), tertiles of body mass index (≤22, 23-24, or ≥24 kg/m2), pigmentary traits and ,for pigmentary traits, mean spring/summer ambient UVB level; further stratified by year of birth (1925-1929, 1930-1934, 1935-1939, 1940-1944, 1945-1950)

(7)

eTable 3: Hazard ratios (HRs) and 95% confidence intervals (CIs) for latitude and mean spring/summer daily ambient UVB level in district of residence at inclusion in relation to risk of differentiated thyroid cancer, stratified by personal history of goiter or nodules, E3N cohort 1993-2008 (n=86,960).

No personal history Personal history

of goiter or nodules of goiter or nodules

Multivariable HR^a Multivariable HR^a

Cases

(n=292) HR 95% CI Cases

(n=68) HR 95% CI Mean spring/summer daily UVB dose

(J/m²)

< 36,060 39 ref 11 ref

36,060 – 37,859 75 1.8 [1.2-2.7] 22 1.7 [0.8-3.6]

37,860 – 43,979 92 2.3 [1.6-3.3] 18 1.4 [0.7-3.0]

≥ 43,980 86 2.2 [1.5-3.2] 17 1.1 [0.5-2.4]

P for linear trend 0.004 0.6

Latitude

< 45.09 85 ref 17 ref

45.09– 47.35 87 1.0 [0.8-1.4] 18 1.1 [0.6-2.2]

47.36 – 48.50 62 0.8 [0.6-1.1] 19 1.4 [0.7-2.6]

≥ 48.51 58 0.7 [0.5-0.9] 14 1.0 [0.5-2.0]

P for linear trend 0.01 0.6

UVB: ultraviolet B

a Adjusted for age, smoking status (ever, current, past), personal history of dysthyroidism (yes, no), tertiles of body mass index (≤22, 23-24, or ≥24 kg/m²) and pigmentary traits. Further stratified by year of birth (1925-1929, 1930-1934, 1935- 1939, 1940-1944, 1945-1950)

(8)

eTable 4: Odds Ratios (ORs) and 95% confidence intervals (CIs) for pigmentary traits and measures of residential UV exposure at inclusion in relation to history of goiter and nodules and history of dysthyroidism. E3N Cohort, 1990-2008 (n=86,960)

History of goiter or nodules History of dysthyroidism

Cases HR^a 95% CI Cases HR^a 95% CI

Number of nevi

Few 1627 1.1 [1.0-1.2] 4552 1.0 [0.9-1.1]

Many 2107 1.2 [1.1-1.3] 5436 1.1 [1.0-1.2]

Very many 629 1.4 [1.2-1.6] 1478 1.2 [1.1-1.3]

Number of freckles

None 1857 ref - 5011 ref -

Few 1160 1.0 [0.9-1.1] 3113 1.01 [0.96-1.07]

Many 1489 1.0 [0.9-1.1] 3898 1.04 [0.99-1.09]

Very many 251 0.9 [0.8-1.1] 689 1.0 [0.9-1.1]

p for linear trend 0. 9 0.1

Hair color

Red 81 1.0 [0.8-1.3] 214 0.9 [0.8-1.1]

Blond 482 1.0 [0.9-1.1] 1292 1.0 [0.9-1.1]

Chestnut 2766 ref - 7555 ref -

Brown/Dark 1428 1.1 [1.0-1.2] 3650 1.02 [0.97-1.07]

Skin complexion

Very fair 65 1.1 [0.8-1.4] 178 1.2 [1.0-1.4]

Fair 2758 1.0 [0.9-1.1] 7335 1.01 [0.96-1.06]

Medium 1875 ref - 4997 ref -

Dark/Very dark 59 0.8 [0.6-1.0] 201 1.0 [0.9-1.2]

Skin sensitivity to sun exposure

(9)

Not sensitive 1034 ref - 2939 ref - Moderately sensitive 2298 1.1 [1.0-1.2] 5920 0.98 [0.93-1.03]

Highly sensitive 1425 1.1 [1.0-1.2] 3852 1.06 [1.00-1.13]

Latitude

< 45.09 1319 ref - 3664 ref -

45.09– 47.35 1205 0.94 [0.87-1.03] 3151 0.84 [0.80-0.89]

47.36 – 48.50 1074 0.91 [0.83-0.99] 2834 0.80 [0.75-0.84]

≥ 48.51 1159 0.90 [0.82-0.97] 3062 0.77 [0.73-0.82]

Mean spring/summer daily ambient UVB level (J/m²)

< 36,060 1013 ref - 2804 ref -

36,060 – 37,859 1229 1.1 [1.0-1.2] 3146 0.99 [0.94-1.05]

37,860 – 43, 979 1166 1.1 [1.0-1.2] 3149 1.06 [1.00-1.12]

≥ 43,980 1349 1.2 [1.1-1.3] 3612 1.23 [1.16-1.30]

UV: ultraviolet

aAdjusted for age, smoking status (ever, current, past), tertiles of body mass index (≤22, 23-24, or ≥24 kg/m²), personal history of dysthyroidism (yes, no) for personal history of goiter or nodules, personal history of goiter or nodules (yes, no) for personal history of dysthyroidism, stratified by year of birth (1925-1929, 1930-1934, 1935-1939, 1940-1944, 1945-1950), further adjusted for pigmentary traits and ,for pigmentary traits, mean

spring/summer ambient UVB level

(10)

eFigure 1

Mean level of spring/summer daily UVB dose (J/m²)

< 36,060 36,060 – 37,859 37,860 – 43,979

≥ 43,980 Mean latitude

< 45.08 45.08– 47.34 47.35 – 48.50

≥ 48.51

Number of women by county (from 4772 (Paris) to 8 (South Corsica))

3500 1300 700 8 4772 2000

A

B

(11)

eFigure 2

1998

147-179 180-229

129-1461

104-128

-

2003

191-238 152-190 131-151 113-130

2008

185-234 153-184 138-152 117-137

2014

184-246 157-183 143-156 126-142

1990

104-123 161-208 124-160 85-104

2003

16.7-20.4 12.7-16.8 11.5-12.6 9-11.4

2008

17.2-20.4 13.0-17.1 12.2-12.9 10.3-12.1

2014

183.5-245.

156.5-183.4 142.3-156.4 125.9-142.2