Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million ...genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients ...and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P
<3 × 10
): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10
) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.
Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 ...Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: ∼25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5′ end of
TNRC9
, a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and ...rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10−12 for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Assessing thyroid cancer risk using polygenic risk scores Liyanarachchi, Sandya; Gudmundsson, Julius; Ferkingstad, Egil ...
Proceedings of the National Academy of Sciences - PNAS,
03/2020, Letnik:
117, Številka:
11
Journal Article
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Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants ...with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10−9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4–8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.
To evaluate cancer incidence among licenced commercial pilots in association with cosmic radiation.
Cohort study where ionizing radiation dose of cosmic radiation was estimated from airline data and ...software program and cancer incidence was obtained by record linkage with nation-wide cancer registry. All licenced commercial male airline pilots were followed from 1955 to 2015, ever or never employed at airline with international routes. Standardized incidence ratios were calculated and relative risk by Poisson regression, to examine exposure-response relation.
Eighty three cancers were registered compared with 92 expected; standardized incidence ratios were 0.90 (95% CI 0.71 to 1.11) for all cancers, 3.31 (95% CI 1.33 to 6.81) for malignant melanoma, and 2.49 (95% CI 1.69 to 3.54), for basal cell carcinoma of skin. The risk for all cancers, malignant melanoma, prostate cancer, basal cell carcinoma of skin, and basal cell carcinoma of trunk increased with an increase in number of employment years, cumulative air hours, total cumulative radiation dose, and cumulative radiation dose sustained up to age of 40 years. The relative risk for the highest exposure categories of cumulative radiation dose were 2.42 (95% CI 1.50 to 3.92) for all cancers, 2.57 (95% CI 1.18 to 5.56) for prostate cancer, 9.88 (95% CI 1.57 to 190.78) for malignant melanoma, 3.61 (95% CI 1.64 to 8.48) for all basal cell carcinoma, and 6.65 (95% CI 1.61 to 44.64) for basal cell carcinoma of trunk.
This study was underpowered to study brain cancer and leukaemia risk. Basal cell carcinoma of skin is radiation-related cancer, and may be attributed to cosmic radiation. Further studies are needed to clarify the risk of cancers in association with cosmic radiation, other workplace exposure, host factors, and leisure sun-exposure, as clothes, and glass in cockpit windows shield pilots from the most potent ultraviolet-radiation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a ...replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objectives: To study whether increased cancer risk, particularly of cancer types previously related to radiation, was found among cabin attendants, using employment time as a surrogate of exposure to ...cosmic radiation. Methods: A cohort of 1690 cabin attendants, 158 men and 1532 women from the Icelandic Cabin Crew Association and two airline companies in Iceland, was established. Cancer sites were ascertained between 1955 and 1997 by follow-up in a cancer registry. The personal identification number of each subject was used in record linkage to population-based registers containing vital and emigration status, reproductive factors and histologically verified cancer diagnosis. Standardized incidence rates (SIR) of different cancer sites in relation to employment time and year of hiring were calculated, as well as predictive values of breast cancer risk for evaluating possible confounding due to reproductive factors. Results: The total number of person-years was 27,148. Among the women, 64 cancers were observed whereas 51.63 were expected (SIR 1.2, 95% CI 1.0-1.6), and significantly increased risk for malignant melanoma (SIR 3.0, 95% CI 1.2-6.2) was found. Significantly increased risks of overall cancers (SIR 1.3, 95% CI 1.0-1.8) and breast cancer (SIR 1.6, 95% CI 1.0-2.4) were observed among the female cabin attendants when 15 years lag time was applied. Those hired in 1971 or later had the heaviest exposure to cosmic radiation at a young age and had significantly increased risk of overall cancer (SIR 2.8, 95% CI 1.4-4.9) and breast cancer (SIR 4.1, 95% CI 1.7-8.5). Predictive values calculated on the basis of reproductive factors among the cabin attendants and the population, and risk of breast cancer were 1.0 for parous vs. nulliparous, 1.0 for number of children, and 1.1 for age at birth of first child. Conclusion: The increased risk of breast cancer and malignant melanoma among cabin attendants seems to be occupationally related. The part played by occupational exposures, i.e. cosmic radiation, disturbance of the circadian rhythm, and electromagnetic fields or combination of these factors in the etiology of breast cancer among the cabin crew, is still a puzzle as confounding due to parity appears to be ruled out. The relationship between the sunbathing habits of the cabin crew and the increased risk of malignant melanoma needs to be clarified. There is also an urgent need to elucidate the importance of these findings for today's aviation.
Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 ...missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio OR = 1.82, 95% confidence interval CI 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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