BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Study Subjects
4.2. Data Collection
- to provide information on their BRCA1/2 mutational status and, whenever possible, provide the complete report of the genetic test;
- to complete a questionnaire on their medical history and major cancer risk factors, including menstrual history, reproductive and behavioral factors;
- to attend a clinic examination for anthropometric and body composition measurements;
- to provide a 20 mL blood sample for metabolic and hormonal assays;
- to provide information on their health status, and to allow the study officials to contact their usual physicians, to consult clinical notes and to examine biopsy material, as necessary;
- to complete a 24-h food frequency diary of the previous day and the validated 14-point MEDAS questionnaire [26].
4.3. Laboratory Methods
4.4. Nomenclature and Classification of Variants
- loss of function (LOF) variants, including frameshift, nonsense, large deletion and spliceogenic variants, introducing a premature termination codon (PTC) or leading to the in-frame loss of gene regions coding for functional domains;
- nonsynonymous variants, including missense and small in -rame deletion.
4.5. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Characteristics | Total Population (438) | BRCA1 (269) | BRCA2 (169) | p Value * | |
---|---|---|---|---|---|
Age (years) | 46.9 ± 11.1 | 47.2 ± 10.8 | 46.6 ± 11.5 | 0.53 | |
Pathogenic variants (%) LOF Nonsynonymous | 85.6 14.4 | 82.9 17.1 | 89.9 10.1 | 0.004 | |
BRCA1 variant group (%) | N/A | 17.1 2.2 46.1 34.6 | N/A | ||
NONSYNONYMOUS | |||||
LOF | 5′-end | ||||
Inner | |||||
3′-end | |||||
BRCA2 variant group (%) NONSYNONYMOUS | N/A | N/A | 10.1 1.8 46.7 41.4 | ||
LOF | 5′-end | ||||
Inner | |||||
3′-end | |||||
Education (%) | |||||
First level Second level Third level | 16.7 44.5 38.8 | 17.1 44.6 38.3 | 16.0 44.4 39.6 | 0.94 | |
Menarche (yrs) | 12.4 ± 1.4 | 12.3 ± 1.5 | 12.4 ± 1.4 | 0.43 | |
Age at first live birth (yrs) | 29.0 ± 4.9 | 28.7 ± 4.9 | 29.4 ± 4.8 | 0.21 | |
Pregnancy (yes) (%) | 71.0 | 73.2 | 66.5 | 0.20 | |
Number of children (%) 1 ≥2 | 30.7 69.3 | 28.6 71.4 | 34.3 65.7 | 0.31 | |
Menopause (%) | 72.9 | 72.5 | 73.4 | 0.73 | |
Natural menopause (%) | 25.1 | 23.6 | 27.4 | 0.44 | |
Oral contraceptive use in the past (%) | 67.8 | 66.5 | 70.0 | 0.47 | |
Smoke in the past (%) | 27.3 | 27.5 | 27.0 | 0.79 | |
Total affected (262) | BRCA 1 (163) | BRCA 2 (99) | |||
Cancer type (% if affected) Breast Breast and ovarian Ovarian | 82.1 4.2 13.7 | 79.1 4.9 16.0 | 86.9 3.0 10.1 | 0.29 | |
Age at diagnosis (years) | 44.0 ± 8.7 | 43.5 ± 9.1 | 44.7 ± 8.1 | 0.31 | |
Breast cancer (215) | BRCA1 (129) | BRCA2 (86) | |||
Infiltrating duct (%) ER-negative (%) Axillary node metastasis (%) Ki-67 > 14 (%) | 86.0 44.6 31.6 87.2 | 88.1 58.8 25.6 94.0 | 82.9 24.1 40.7 78.5 | 0.01 <0.001 0.02 0.005 |
All Cancers | BRCA1 163 Affected and 106 Unaffected | BRCA2 99 Affected and 70 Unaffected |
---|---|---|
OR (95% CI) * | OR (95% CI) * | |
Nonsynonymous LOF | 1 1.53 (0.80–2.92) | 1 1.14 (0.40–3.22) |
Breast Cancer | BRCA1 129 affected and 106 unaffected | BRCA2 86 affected and 70 unaffected |
OR (95% CI) * | OR (95% CI) * | |
Nonsynonymous LOF | 1 1.42 (0.71–2.82) | 1 0.90 (0.31–2.66) |
Metabolic Characteristics | Nonsynonymous (63) | LOF (375) | P * |
---|---|---|---|
Weight (kg) | 67.0 (2.2) | 64.2 (0.7) | 0.18 |
BMI (kg/m2) | 25.7 (0.8) | 24.5 (0.3) | 0.13 |
Waist circumference (cm) | 78.7 (1.4) | 78.6 (0.7) | 0.93 |
Hip circumference (cm) | 101.3 (1.1) | 99.9 (0.5) | 0.39 |
Waist to height ratio (cm/cm) | 0.49 (0.01) | 0.49 (0.01) | 0.79 |
Fat mass (%) | 30.6 (1.0) | 31.5 (0.5) | 0.65 |
Systolic pressure (mmHg) | 122.0 (1.9) | 125.5 (0.9) | 0.06 |
Diastolic pressure (mmHg) | 81.0 (1.4) | 81.6 (0.6) | 0.56 |
Glycemia (mg/dL) | 97.2 (2.7) | 101.5 (1.2) | 0.03 |
Total cholesterol (mg/dL) | 197.5 (4.3) | 200.1 (2.1) | 0.81 |
HDL cholesterol (mg/dL) | 67.8 (2.2) | 67.9 (0.9) | 0.90 |
LDL cholesterol (mg/dL) | 116.0 (4.0) | 119.0 (1.9) | 0.96 |
Triglycerides (mg/dL) | 107.8 (13.4) | 103.2 (2.8) | 0.46 |
IGF-I (ng/mL) | 182.6 (7.7) | 177.9(3.6) | 0.66 |
Insulin (µIU/mL) | 16.5 (1.3) | 21.2 (1.0) | <0.001 |
Metabolic Characteristics | Total Study Population 375 LOF vs. 63 Nonsynonymous | BC Affected and Unaffected 332 LOF vs. 59 Nonsynonymous |
---|---|---|
BMI (kg/m2) | OR (95% CI) * | OR (95% CI) * |
≤23.4 >23.4 | 1 0.66 (0.37–1.15) | 1 0.62 (0.35–1.11) |
Fat mass (%) | ||
<30 ≥30 | 1 1.01 (0.55–1.83) | 1 1.05 (0.57–1.93) |
Waist to height ratio (cm/cm) | ||
≤0.50 >0.50 | 1 1.34 (0.70–2.55) | 1 1.41 (0.74–2.69) |
Waist circumference (cm) | ||
<85 ≥85 | 1 1.10 (0.55–2.15) | 1 1.20 (0.60–2.39) |
Glycemia (mg/dL) | ||
<110 ≥110 | 1 1.54 (0.80–2.97) | 1 1.75 (0.90–3.42) |
HDL cholesterol (mg/dL) | ||
<50 ≥50 | 1 1.45 (0.69–3.60) | 1 1.58 (0.59–4.23) |
Triglycerides (mg/dL) | ||
<150 ≥150 | 1 1.07 (0.47–2.46) | 1 1.21 (0.51–2.89) |
Blood pressure (mmHg) | ||
<130/85 ≥130/85 | 1 1.43 (0.80–2.49) | 1 1.57 (0.87–2.83) |
Insulin (µIU/mL) | ||
1 (1.0–10.5) 2 (10.6–23.3) 3 (23.4–101.2) | 1 1.26 (0.64–1.54) 1.91 (0.90–4.03) | 1 1.41 (0.70–2.86) 2.42 (1.12–5.23) |
IGF-I (ng/mL) | ||
1 (60.3–140.7) 2 (140.8–199.5) 3 (199.6–508.1) | 1 0.63 (0.31–1.29) 1.07 (0.47–2.43) | 1 0.48 (0.23–1.02) 0.72 (0.33–1.57) |
Variant Position | Number (N) | BRCA-Related Cancer OR * (95% CI) | BRCA–Related BC OR * (95% CI) | |||||
---|---|---|---|---|---|---|---|---|
BRCA1 | N Total 269 | N Affected 163 | p | N Affected 129 | p | |||
Nonsynonymous | 46 6 124 93 | 24 5 76 58 | 1 4.49 (0.46–44.1) 1.32 (0.65–2.70) 1.44 (0.65–3.16) | 0.20 0.44 0.37 | 20 5 58 46 | 1 4.97 (0.51–48.4) 1.25 (0.59–2.60) 1.30 (0.56–2.98) | 0.19 0.56 0.54 | |
LOF | 5′-end Inner 3′-end | |||||||
BRCA2 | 169 | 99 | OR (95% CI) | p | 86 | OR (95% CI) | p | |
Nonsynonymous | 17 3 79 70 | 10 3 44 42 | 1 NA 1.09 (0.33–3.60) 1.27(0.39–4.16) | 0.88 0.69 | 10 3 34 39 | 1 NA 0.86 (0.26–2.82) 1.07 (0.33–3.55) | 0.78 0.91 | |
LOF | 5′-end Inner 3′-end |
Metabolic Characteristics | BRCA1 (269) | BRCA2 (169) | ||||||
---|---|---|---|---|---|---|---|---|
Nonsynonymous (46) | LOF-5′ End (6) | LOF-Inner (124) | LOF-3′ End (93) | Nonsynonymous (17) | LOF-5′ End (3) | LOF-Inner (79) | LOF-3′ End (70) | |
Weight (kg) | 65.8 (2.0) | 66.0 (5.7) | 63.9 (1.2) | 65.8 (1.4) | 70.5 (3.3) | 61.1 (7.9) | 64.8 (1.5) | 61.9 (1.6) |
BMI (kg/m2) | 25.4 (0.8) | 25.1 (2.2) | 24.3 (0.5) | 25.2 (0.6) | 26.4 (1.2) | 23.1 (2.9) | 24.9 (0.6) | 23.5 (0.6) |
Waist circumference (cm) | 76.8 (1.8) | 79.9 (4.9) | 78.3 (1.1) | 80.1 (1.2) | 83.5 (3.5) | 74.5 (8.3) | 80.1 (1.6) | 75.6 (1.7) |
Hip circumference (cm) | 100.1 (1.5) | 100.8 (4.2) | 100.1 (0.9) | 100.9 (1.1) | 104.3 (2.4) | 101.2 (5.7) | 99.8 (1.1) | 98.2 (1.2) |
Waist to height ratio (cm/cm) | 0.48 (0.01) | 0.49 (0.03) | 0.48 (0.01) | 0.50 (0.01) | 0.51 (0.02) | 0.46 (0.05) | 0.50 (0.01) | 0.47 (0.01) |
Fat mass (%) | 29.7 (1.2) | 33.4 (3.4) | 30.5 (0.8) | 33.5 (0.8) | 33.4 (2.3) | 38.0 (4.9) | 31.5 (1.0) | 29.8 (1.1) |
Systolic pressure (mmHg) | 122.0 (2.4) | 121.8 (6.6) | 127.8 (1.5) | 123.7 (1.8) | 122.1 (3.8) | 110.0 (15.6) | 124.8 (1.8) | 124.9 (1.9) |
Diastolic pressure (mmHg) | 82.2 (1.5) | 83.2 (4.2) | 82.9 (0.9) | 80.3 (1.1) | 78.1 (2.6) | 90.0 (10.7) | 81.4 (1.2) * | 80.9 (1.3) ** |
Glycemia (mg/dL) | 101.1 (3.2) | 96.5 (8.8) | 104.2 (1.9) | 98.9 (2.2) | 86.6 (5.7) | 94.0 (13.6) | 99.5 (2.6) ** | 103.3 (2.8) ** |
Total cholesterol (mg/dL) | 198.6 (5.7) | 196.7 (15.8) | 203.2 (3.5) | 201.0 (4.0) | 194.5 (9.6) | 194.3 (22.8) | 198.2 (4.4) | 195.9 (4.7) |
HDL cholesterol (mg/dL) | 68.4 (2.4) | 60.2 (6.6) | 69.9.3 (1.5) | 66.3 (1.7) | 66.2 (4.2) | 83.7 (10.1) | 62.1 (1.9) | 72.4 (2.1) |
LDL cholesterol (mg/dL) | 115.9 (5.2) | 124.3 (14.3) | 119.0 (3.1) | 123.3 (3.6) | 116.2 (9.1) | 105.3 (21.6) | 122.3 (4.2) | 109.8 (4.5) |
Triglycerides (mg/dL) | 109.4 (10.6) | 98.5 (29.5) | 105.6 (6.5) | 105.5 (7.5) | 102.1 (12.0) | 61.3 (28.6) | 108.3 (5.6) | 92.3 (5.9) |
IGF-I (ng/mL) | 186.8 (8.4) | 136.5 (25.4) | 182.5 (5.2) | 175.6 (6.0) | 170.6 (17.1) | 139.9 (39.5) | 178.7 (7.8) | 176.6 (8.3) |
Insulin (µIU/mL) | 17.9 (2.7) | 24.5 (8.3) | 22.5 (1.7) | 19.6 (1.9)* | 12.6 (4.6) | 21.3 (10.7) | 19.7 (2.1) ** | 22.3 (2.3) ** |
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Oliverio, A.; Bruno, E.; Colombo, M.; Paradiso, A.; Tommasi, S.; Daniele, A.; Terribile, D.A.; Magno, S.; Guarino, D.; Manoukian, S.; et al. BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers. Cancers 2020, 12, 3584. https://doi.org/10.3390/cancers12123584
Oliverio A, Bruno E, Colombo M, Paradiso A, Tommasi S, Daniele A, Terribile DA, Magno S, Guarino D, Manoukian S, et al. BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers. Cancers. 2020; 12(12):3584. https://doi.org/10.3390/cancers12123584
Chicago/Turabian StyleOliverio, Andreina, Eleonora Bruno, Mara Colombo, Angelo Paradiso, Stefania Tommasi, Antonella Daniele, Daniela Andreina Terribile, Stefano Magno, Donatella Guarino, Siranoush Manoukian, and et al. 2020. "BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers" Cancers 12, no. 12: 3584. https://doi.org/10.3390/cancers12123584