KLHDC8B in Hodgkin lymphoma and possibly twinning

Abstract

A key feature of Hodgkin lymphoma is that the malignant cells are binucleated, as a consequence of failed cytokinesis. We recently ascertained a family in which multiple cases of Hodgkin lymphoma had occurred among individuals who inherited a balanced chromosomal translocation. We cloned the translocation breakpoints and found that it disrupted a previously uncharacterized gene, KLHDC8B, encoding a Kelch family protein whose deficiency impairs cytokinesis and leads to binucleated cells. In other families we found a rare single nucleotide polymorphism affecting mitotic translation of KLHDC8B that was associated with and linked to Hodgkin lymphoma. Interestingly, the index family demonstrated an unusual frequency of twins, and there is a previously reported association between Hodgkin lymphoma and twins. Here we review the unusual genetic features of Hodgkin lymphoma, including gender concordance among siblings, and genetically test the hypothesis that KLHDC8B may participate in twinning by disrupting cytokinesis through impediment of polar body separation from oocytes.

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Acknowledgements

AET is supported by NIH T32GM007454. We thank the families for their participation.

Figures and Tables

Figure 1 Gender concordance in familial Hodgkin lymphoma. (A) Mickey Mantle and his four sons. (Photo courtesy of Danny Mantle). (B) Pedigree of the Mantle family. Hodgkin (HL, black) or non-Hodgkin lymphoma (NHL, grey). HCC, hepatocellular carcinoma.

Figure 2 Graphical representation of polar body twinning and its implication in allele sharing. We compare allele sharing in first and second polar body twins (twin B) with a conventionally conceived twin (twin A). In each twin there is a 50% chance of sharing paternally derived alleles (represented by light and dark blue). However, the sharing of maternally derived alleles (represented by red and pink) is determined by which polar body is fertilized and the location and frequency of chiasmata. (Crossing-over is not depicted during spermatogenesis).

Table 1 Expected and observed allele sharing at centromeric regions throughout the genome indicative of twin type

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