| 1. |
- Ajore, Ram, et al.
(författare)
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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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| 2. |
- Ali, Mina, et al.
(författare)
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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 1649-
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined = 2.5 × 10−27; βcombined = −0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause–effect relationship. Our results provide mechanistic insight into MM predisposition.
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| 3. |
- Anwar, Wagida A, et al.
(författare)
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Consanguinity and genetic diseases in North Africa and immigrants to Europe.
- 2014
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Ingår i: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 24 Suppl 1, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- Endemic diseases are caused by environmental and genetic factors. While in this special issue several chapters deal with environmental factors, including infections, the present focus is on genetic causes of disease clustering due to inbreeding and recessive disease mechanisms. Consanguinity is implying sharing of genetic heritage because of marriage between close relatives originating from a common ancestor. With limited natural selection, recessive genes may become more frequent in an inbred compared with an outbred population. Consanguinity is common in North Africa (NA), and the estimates range from 40 to 49% of all marriages in Tunisia and 29-33% in Morocco. As a consequence, recessive disorders are common in the NA region, and we give some examples. Thalassaemia and sickle cell disease/anaemia constitute the most common inherited recessive disorders globally and they are common in NA, but with immigration they have spread to Europe and to other parts of the world. Another example is familial Mediterranean fever, which is common in the Eastern Mediterranean area. With immigrantion from that area to Sweden, it has become the most common hereditary autoinflammatory disease in that country, and there is no evidence that any native Swede would have been diagnosed with this disease. The examples discussed in this chapter show that the historic movement of populations and current immigration are influencing the concept of 'endemic' disease.
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| 4. |
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| 6. |
- Bermejo, Justo Lorenzo, et al.
(författare)
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Age-time risk patterns of solid cancers in 60 901 non-Hodgkin lymphoma survivors from Finland, Norway and Sweden
- 2014
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 164:5, s. 675-683
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Tidskriftsartikel (refereegranskat)abstract
- Survival after non-Hodgkin lymphoma (NHL) has increased thanks to improved treatment but NHL survivors have an increased risk of second neoplasms. The assessment of cancer risk patterns after NHL may help to quantify the late side-effects of therapy. Poisson regression was used to estimate relative risks (RRs) and absolute incidence rates for nine solid tumours based on a nationwide cohort of 60 901 NHL survivors from Finland, Norway and Sweden. Patients were diagnosed between 1980 and 2006 and developed 6815 s neoplasms. NHL patients showed an increased risk of each of the nine investigated cancer sites: prostate and pancreas (both RRs 1.28), breast (1.37), colorectum (1.48), urinary bladder (1.52), stomach and lung (both RRs 1.87), skin (melanoma 2.27) and kidney (2.56). The RRs showed a U-shaped relationship with time after NHL for all nine-second cancer types. NHL diagnosis early in life was a risk factor for the development of second cancers with the exception of melanoma, but a risk excess was even observed in patients diagnosed with NHL at age 80+ years. The present study provides accurate estimates on the adverse late effects of NHL therapy, which should guide the establishment of cancer prevention strategies in NHL survivors.
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| 7. |
- Bevier, Melanie, et al.
(författare)
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Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer?
- 2011
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 47:4, s. 586-591
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Tidskriftsartikel (refereegranskat)abstract
- Background: Age at first and last birth and the number of children are known to influence the risk of endometrial and ovarian cancers. However, it remains unknown whether the difference in years between first and last childbirth plays a role. The Swedish Family-Cancer Database allowed us to carry out the largest study ever on reproductive factors in these cancers. Material and methods: We selected over 5.7 million women from the database. We estimated the effect of number of children, age at birth and difference between age at first and last birth by Poisson regression adjusted for age, period, region and socioeconomic status. Results: The risk for endometrial cancer is negatively associated with increasing number of children and increasing age at first as well as age at last birth. Weaker associations are found for ovarian cancer. Age at last birth is the factor that shows highest influence. A large difference in first and last childbirth shows a protective effect on the risk of endometrial cancer. Conclusion: Our findings suggest that the risk of endometrial cancer is significantly decreased for women having at least a difference of 10 years between their first and last birth. Ovarian cancer does not seem to be influenced by the time interval between first and last birth. (c) 2010 Elsevier Ltd. All rights reserved.
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| 8. |
- Bevier, Melanie, et al.
(författare)
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Incidence of cancer of unknown primary in Sweden: analysis by location of metastasis.
- 2012
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Ingår i: European Journal of Cancer Prevention. - 1473-5709. ; 21:6, s. 596-601
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Tidskriftsartikel (refereegranskat)abstract
- Increasing incidences of cancer of unknown primary (CUP) have been observed in Sweden previously. However, it is not known how the incidence trends for specific locations of metastasis vary. Site-specific data are available on the basis of the ninth international classification of diseases. CUP patients were identified between 1987 and 2008 from the Swedish Family-Cancer Database. Malignant neoplasms of ill-defined sites were diagnosed in 4042 patients, 1976 developed metastasis in lymph nodes, 9615 had metastasis in specified organs, and in 8052 patients, the malignant neoplasm was diagnosed without further specification. Age-standardized incidence rates for 23 685 patients were analyzed using a direct method of standardization. Overall, the incidence of CUP decreased from 6.98 to 6.00 per 100 000 from 1987 to 2008. The number of patients diagnosed with metastasis in specified organs decreased, whereas the number of patients diagnosed with CUP without further specification increased from 2.65 to 3.02 per 100 000. With improvements in diagnostic methods and imaging techniques for identification of cancer, the incidences of CUP have been decreasing because primary tumors can be specified more often. Computed tomography is typically sensitive in detecting lung, kidney, and colorectal cancers, which are known to have a genetic link with CUP. Prostate-specific antigen testing is used to detect prostate cancer, for which bone is a common metastatic site. Liver metastases are common if the primary tumor is located in the colorectum. If the primary tumor is found, this cancer site replaces the diagnosis of CUP within the Cancer Register and therefore CUP incidence is decreased.
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| 9. |
- Bevier, Melanie, et al.
(författare)
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Influence of family size and birth order on risk of cancer: a population-based study
- 2011
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Family size and birth order are known to influence the risk of some cancers. However, it is still unknown whether these effects change from early to later adulthood. We used the data of the Swedish Family Cancer Database to further analyze these effects. Methods: We selected over 5.7 million offspring with identified parents but no parental cancer. We estimated the effect of birth order and family size by Poisson regression adjusted for age, sex, period, region and socioeconomic status. We divided the age at diagnosis in two groups, below and over 50 years, to identify the effect of family size and birth order for different age periods. Results: Negative associations for increasing birth order were found for endometrial, testicular, skin, thyroid and connective tissue cancers and melanoma. In contrast, we observed positive association between birth order and lung, male and female genital cancers. Family size was associated with decreasing risk for endometrial and testicular cancers, melanoma and squamous cell carcinoma; risk was increased for leukemia and nervous system cancer. The effect of birth order decreased for lung and endometrial cancer from age at diagnosis below to over 50 years. Combined effects for birth order and family size were marginally significant for thyroid gland tumors. Especially, the relative risk for follicular thyroid gland tumors was significantly decreased for increasing birth order. Conclusion: Our findings suggest that the effect of birth order decreases from early to late adulthood for lung and endometrial cancer.
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| 10. |
- Bevier, Melanie, et al.
(författare)
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Risk of breast cancer in families of multiple affected women and men
- 2012
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 132:2, s. 723-728
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Tidskriftsartikel (refereegranskat)abstract
- Family history of first and second-degree relatives is known to increase the risk for breast cancer. Less data are available on the risks between defined multiple affected close and distant relatives for which the reliability of data may be an issue. Data on affected males are sparse. These questions and the probable genetic models were addressed in this study by means of a nationwide Swedish Family-Cancer Database. We estimated the effect of family history of breast cancer by Poisson regression for women of at least 30 years of age after adjusting for age, period, region, socioeconomic status, number of children, and age at first birth. The results of the study showed that relative risk (RR) for breast cancer was associated with a first degree as well as second-degree family history. Having at least two female affected first-degree relatives increased the RR at least to 2.8, favoring an additive interaction. The risk was increased around ten times in women with both parents affected. When either a father or a mother was affected, the RRs were nearly identical (RR = 1.73 and 1.74, respectively). The RR for a woman increased more when a brother was affected (RR = 2.48) compared to when a sister was affected (RR = 1.87). Having an affected grandmother showed lower familial excess risks than having an affected half sister (RR = 1.27, and 1.26; and RR = 1.39, and 1.50; respectively, for maternal and paternal relatives). We concluded that when both parents were diagnosed with breast cancer, the risk for the daughter was increased tenfold. Having an affected brother showed a somewhat higher risk than having an affected sister. The data suggest that male breast cancer has a higher genetic basis than female breast cancer, which invites further search of the underlying mechanisms.
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