Concordance for Hodgkin's Disease in Identical Twins Suggesting Genetic Susceptibility to the Young-Adult Form of the Disease

Mack, Thomas M.; Cozen, Wendy; Shibata, Darryl; Weiss, Lawrence M.; Nathwani, Bharat N.; Hernández, A.M.; Taylor, Clive R.; Hamilton, Ann S.; Deapen, Dennis; Rappaport, Edward

doi:10.1056/nejm199502163320701

Cited by 307 publications

(173 citation statements)

References 38 publications

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“…We confirmed and further quantified the strong familial clustering of HL, [1][2][3][4][5][6] being among the highest for any malignancy in the Database; the sibling risk of over 5 ranks second after testicular cancer. 9 The higher risks for siblings compared to parent-offspring pairs suggest a recessive component or childhood shared effects.…”

supporting

confidence: 52%

“…Despite evidence suggesting a familial clustering of Hodgkin's lymphoma (HL), [1][2][3][4][5][6] there is no clear understanding on the relative contribution of genes and shared environmental factors, including childhood infections, 7,8 to familial risk. The rarity of familial HL has hampered a detailed analysis of the familial clustering and it has probably contributed to the variation even in recent risk estimates for first-degree relatives, such as 4.9 from Utah 5 and 3.27 from Iceland.…”

mentioning

confidence: 99%

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The familial risk of Hodgkin's lymphoma ranks among the highest in the Swedish Family-Cancer Database

Altieri

Hemminki

2006

Leukemia

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supporting

confidence: 52%

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confidence: 99%

The familial risk of Hodgkin's lymphoma ranks among the highest in the Swedish Family-Cancer Database

Altieri

Hemminki

2006

Leukemia

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“…29,30 For Hodgkin's disease, a previous study reported a 99-fold risk in monozygotic twins. 31 One may speculate whether the mechanism could be similar to that of leukemia, i.e., spreading of transformed cells between twins who share the placenta. Two aspects deserve comment on breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Cancer risks in twins: Results from the Swedish family‐cancer database

Hemminki

2002

Intl Journal of Cancer

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Twin studies on cancer have addressed two general questions, one about the possible carcinogenic effects of twinning and the second about heritable effects of cancer. The first question is answered by comparing the occurrence of cancer in twins to that in singletons; the second is answered in probandwise analysis of monozygotic twins compared to dizygotic twins or siblings. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and 62,574 0 -66-year-old twins to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for all main cancer compared to cancer in singletons. In probandwise analysis, the SIR was calculated for the co-twin of an affected twin. The overall risk of cancer in same or opposite sex twins was at the level of the risk for singletons. Testicular cancer was increased among same sex twins and all twins to an SIR of 1.43. Melanoma was decreased in these groups of twins to an SIR of 0.84. Some other cancer sites were increased or decreased in some groups of twins, but none in all twins. The SIR of breast cancer was 1.01 and 1.04 in same and opposite sex twins, respectively. Probandwise analysis showed increased risks for Hodgkin's disease in males and breast cancer and childhood acute lymphoid leukemia among females. The data on this unselected population of twins suggest that twinning per se is not a risk factor of cancer. However, because twins are smaller than singletons at birth, some possible effects could be masked by such differences. In utero hormonal exposures may be related to the risk of testicular cancer. The protective effects in melanoma may be due to socioeconomic factors.

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“…2 Specifically, there is strong evidence for genetic factors based on evidence from multiply affected families from case series, twin, case-control, and population-based registry studies. [3][4][5][6][7][8][9] Furthermore, our group analyzed data from registries in Scandinavia and found significant familial aggregation of HL (RR = 3.1) and other lymphoproliferative tumors. Relative risks were higher in men compared with women, in siblings of cases compared with parents and offspring, and in relatives of patients with diagnosis under the age of 40.…”

mentioning

confidence: 99%

“…Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 status and in smaller families; 4) the occurrence of EpsteinBarr virus (EBV) in HL tumor cells and 5) a strong familial risk. 2 Specifically, there is strong evidence for genetic factors based on evidence from multiply affected families from case series, twin, case-control, and population-based registry studies.…”

mentioning

confidence: 99%

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

et al. 2016

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H odgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.

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Concordance for Hodgkin's Disease in Identical Twins Suggesting Genetic Susceptibility to the Young-Adult Form of the Disease

Abstract: Genetic susceptibility underlies Hodgkin's disease in young adulthood.

Cited by 307 publications

References 38 publications

The familial risk of Hodgkin's lymphoma ranks among the highest in the Swedish Family-Cancer Database

The familial risk of Hodgkin's lymphoma ranks among the highest in the Swedish Family-Cancer Database

Cancer risks in twins: Results from the Swedish family‐cancer database

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

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