Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk

Chubb, Daniel; Weinhold, Niels; Broderick, Peter; Chen, Bowang; Johnson, David C.; Försti, Asta; Vijayakrishnan, Jayaram; Migliorini, G; Dobbins, Sara E.; Holroyd, Amy; Hose, Dirk; Walker, Brian A.; Davies, Faith E.; Gregory, Walter A.; Jackson, Graham; Irving, Julie; Pratt, Guy; Fegan, Chris; Fenton, James A. L.; Neben, Kai; Hoffmann, Per; Nöthen, Markus M.; Mühleisen, Thomas W.; Eisele, Lewin; Ross, Fiona; Straka, Christian; Einsele, Hermann; Langer, Christian; Dörner, Elisabeth; Allan, James M.; Jauch, Anna; Morgan, Gareth J.; Hemminki, Kari; Houlston, Richard S.; Goldschmidt, Hartmut

doi:10.1038/ng.2733

Cited by 153 publications

(157 citation statements)

References 49 publications

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“…Thus, the threshold for statistical significance was 0.0028 (0.05/18). For SNP rs10936599 we also conducted a meta-analysis with the results of the study by Chubb et al 7 reaching a total sample size of 6,112 MM cases and 12,905 healthy controls. Finally we also performed a meta-analysis with the results of Hosnijeh et al 39 to better determine the effect of LTL and MM risk.…”

Section: Discussionmentioning

confidence: 99%

“…In addition a susceptibility locus (SNP rs10936599) that lies in the TERC region and was recently reported in a GWAS on MM risk 7 was added to the second phase. Results of the first phase are reported in Supporting Information Tables 1 and 2, while results of the joint analysis of phase 1 and 2 are reported in Table 2.…”

Section: Snp Main Effectmentioning

confidence: 99%

“…3,4 Several risk loci have been proposed and a few have been identified through genomewide association studies (GWAS). 2,[5][6][7][8][9][10][11] The genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) gene regions could play a role in MM etiology for two reasons: first the two genes are responsible for crucial cellular processes, namely telomere homeostasis, second their polymorphic variants have been found to be associated with multiple cancer types and other human phenotypes. [12][13][14][15][16][17][18][19][20][21][22][23][24] TERT and TERC constitute the telomerase complex, 25 whose correct functioning is fundamental for the accurate de novo synthesis of telomeric ends.…”

mentioning

confidence: 99%

“…[22][23][24]34 A very recent GWAS has reported the association of rs10936599 with increased risk of MM. 7 This polymorphism lies in 3q26.2, in a linkage disequilibrium (LD) region that includes also the TERC gene. Clearly this finding further increases the a priori hypothesis of the involvement of the two genes in the disease.…”

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confidence: 99%

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Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Campa

Martino

Várkonyi

et al. 2014

Intl Journal of Cancer

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Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.

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Section: Discussionmentioning

confidence: 99%

Section: Snp Main Effectmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Campa

Martino

Várkonyi

et al. 2014

Intl Journal of Cancer

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“…Potential genes include DNMT3A or CBX7 as they are already implicated in other cancers. 29,30 Given the sample size and the submaximal linkage disequilibrium in these GWAS studies, it is probable that many other genetic loci remain unidentified. 29,30 …”

Section: Aspect 2 Environmental and Inherited Contributionmentioning

confidence: 99%

Understanding the multiple biological aspects leading to myeloma

et al. 2014

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Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study

et al. 2023

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Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full‐blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow‐up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.

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Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk

Cited by 153 publications

References 49 publications

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Understanding the multiple biological aspects leading to myeloma

Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study

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