Advertisement
Article tools
  • View PDF
  • Cite this article
  • E-mail this article
  • Send a letter
  • Information on reuse
  • Standard abbreviations
  • Article usage
Author information
Need help?

Commentary

Donor-associated malignancy in kidney transplant patients

Cai-Bin Cui and David A. Gerber

Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.

Address correspondence to: David A. Gerber, Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, USA. Phone: 919.966.8008; Fax: 919.966.6308; E-mail: david_gerber@med.unc.edu.

First published August 27, 2013

Skin cancer cells with donor genotype have been identified in allogeneic transplant patients; however, the donor contribution to the recipient’s epithelial malignancy remains to be established. In this issue of the JCI, Verneuil et al. provide the first evidence for donor contribution to the malignant epithelium of skin squamous cell carcinoma in a kidney transplant recipient. This case report may have important implications for cancer research and clinical care of long-surviving kidney transplant patients.

See the related Brief Report beginning on page 3797.

Introduction

Kidney transplantation is the preferred treatment for end-stage kidney disease due to improved patient survival and quality of life as well as lower treatment costs compared with dialysis (1). However, as transplant recipients live longer and a greater number of older donors are used (2), long-term complications, such as cancer as a leading cause of death in patients with a functioning graft, will begin to emerge. This outcome can predominantly be attributed to the immunosuppression required to avoid rejection of the transplanted organ (3). The incidence of skin cancer is increased in transplant recipients, especially in kidney transplant recipients (KTRs), for which squamous cell carcinoma (SCC) is most common (46).

In most cases, skin SCC originates from the recipient’s epithelium, but donor cells from transplanted kidney could also be a source. While more than 64 cases of donor cell leukemia have been reported in bone marrow transplant patients (7), only one skin basal cell carcinoma (BCC) has been previously reported as being donor associated in allogeneic KTR (8). In this issue of the JCI, Verneuil et al. provide the first convincing evidence for a direct donor contribution to the malignant epithelium of skin SCC in a KTR (9).

Skin carcinogenesis

In contrast to the prevalence of BCC in the general population, skin SCC is predominant in KTRs (4, 10). Skin SCC is a fully differentiated type of skin carcinoma originating mainly from epithelium and is the most common skin cancer in transplant recipients, occurring 65 to 250 times as frequently as in the general population (4, 6). Skin carcinogenesis in KTRs is a complex, incompletely understood process. Multiple oncogenic events include gene mutations (e.g., TP53, which encodes p53, and KRAS) introduced by UV radiation (3, 11), viral infection, or germline inheritance. More than 250 independent germline TP53 mutations have been discovered (12). Such mutations are typically associated with Li-Fraumeni syndrome, a clinically and genetically heterogeneous autosomal-dominant inherited cancer syndrome (12, 13). Immunosuppressive medications prevent the immune system from removing the mutant cancer cells, which — combined with the deleterious synergistic effects of UV (8, 11) and other events — may initiate and/or promote the process of skin carcinogenesis (3, 13, 14).

Donor-associated versus de novo malignancy in transplant recipients

The majority of skin SCCs in KTRs originate from the recipient’s skin epithelium, but donor cells from the transplanted kidney can also serve as a source. Verneuil et al. (9) reviewed 21 skin SCCs from KTRs; in one patient, they identified a skin SCC with donor genotype, but not the recipient’s. They confirmed that the microdissected p53+ cells in both recipient skin SCC and donor renal tubules had the same mitochondrial DNA–high-resolution melting patterns in all three markers, but were different from the recipient’s DNA. In addition, they found that the skin SCC carried the same TP53 c.524G>A mutation (p.Arg175His, also known as rs28934578) as in donor renal tubule p53+ cells, but not in the normal recipient cells. This germline mutation in TP53 was different from the common UV-induced tandem CC>TT mutation. The authors conclude that the recipient’s skin SCC originated from donor renal tubule cells and provide convincing evidence for direct donor contribution to the malignant epithelium of skin SCC in a KTR. They also identified a KRAS mutation in skin SCC, but not in donor cells, which indicates that the KRAS mutation is a new somatic mutation. The patient skin SCC was located in a UV-exposed area, and the combination of KRAS and TP53 mutations could be a key to initiation and/or promotion of skin epithelial carcinogenesis.

Although it is unclear how donor renal cells migrate to skin and form a tumor, donor-associated malignancy (DAM) should perhaps be approached differently than de novo malignancy (DNM) in a transplant recipient. Because donor cells migrate to new foreign sites, such as recipient skin, it is important to determine how they adapt to the new microenvironmental niche, what effects result from the new interactions, and the effects of donor cells on tumorigenesis. Similar to donor cell leukemia (15), there is undoubtedly some mechanistic overlap between the development of DAM and DNM. In the pathogenesis of DAM, it is important to consider that its cause is multifactorial in nature. Factors intrinsic to the cell and external signaling cues from the niche determine a normal versus neoplastic fate for the transplanted donor cells. Continued research to characterize DAM will help to understand the dynamic equilibrium between both normal and cancer stem cells and the skin microenvironment (7, 15). These interactions could help explain why the p53+ renal tubule cells with the same TP53 mutation in the KTR described by Verneuil et al. never formed a renal tumor (9).

Unanswered questions

Cancer, especially skin SCC, is a leading cause of mortality and morbidity in long-surviving KTRs. Future research should address what can be done to reduce/prevent DNM and DAM in KTRs. Should a cancer risk genetic test be included in transplant recipient and/or donor organ screening? For recipient screenings, biochemical, but not genetic, cancer screenings have been included in the screening guidelines for KTRs (16). Genetic factors are increasingly recognized to play important roles in tumorigenesis. Furthermore, genetic cancer risk screening of transplant recipients is potentially reasonable, since the cost and turnaround time for genetic testing is rapidly improving (17). For donor organ screening, current screening does not include genetic testing for cancer risk gene mutations. It is unclear whether the current report of DAM (9) should prompt a change in the screening approach. The likelihood of performing genetic testing on donor organs is remote at this point, due to the extremely low prevalence of DAM, the long turnaround time, the high cost associated with the genetic tests, and the ever-increasing clinical shortage of donor organs.

Other factors, including organ preservation techniques, contribute to donor cell migration to other organs. Longer cold ischemia time increases the apoptosis of the renal tubules, and more cells and cell debris are shed into the bloodstream. Reducing shedding of donor tissue cells into circulation will reduce homing of donor cells to recipient skin, thereby reducing the possibilities of carcinogenesis (18).

In summary, the increase in long-term survival for solid organ transplant recipients and the knowledge of germline mutations and their association with oncogenesis brings us to a new clinical decision point. While the majority of post-transplant malignancies are likely to remain a de novo malignancy, we may be at the beginning of a time when we can risk assess the possibility of DAM development in a transplant recipient.

Acknowledgments

We thank Chengwen Li (University of North Carolina at Chapel Hill) and Xin-Hai Pei (University of Miami) for their critical comments.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Citation for this article:J Clin Invest. 2013;123(9):3708–3709. doi:10.1172/JCI70438.

See the related Brief Report beginning on page 3797.

References

  1. First MR, Gerber DA, Hariharan S, Kaufman DB, Shapiro R. Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management. Transplantation. 2002;73(3):379–386.
    View this article via: PubMed CrossRef
  2. Gallagher MP, et al. Long-term cancer risk of immunosuppressive regimens after kidney transplantation. J Am Soc Nephrol. 2010;21(5):852–858.
    View this article via: PubMed CrossRef
  3. Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer. 2009;125(8):1747–1754.
    View this article via: PubMed CrossRef
  4. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348(17):1681–1691.
    View this article via: PubMed CrossRef
  5. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143(3):513–519.
    View this article via: PubMed
  6. Jensen P, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40(2 pt 1):177–186.
    View this article via: PubMed CrossRef
  7. Wiseman DH. Donor cell leukemia: a review. Biol Blood Marrow Transplant. 2011;17(6):771–789.
    View this article via: PubMed CrossRef
  8. Aractingi S, et al. Skin carcinoma arising from donor cells in a kidney transplant recipient. Cancer Res. 2005;65(5):1755–1760.
    View this article via: PubMed CrossRef
  9. Verneuil L, et al. Human skin carcinoma arising from kidney transplant–derived tumor cells. J Clin Invest. 2013;123(9):3797–3801.
    View this article via: JCI.org CrossRef
  10. Moloney FJ, Comber H, O’Lorcain P, O’Kelly P, Conlon PJ, Murphy GM. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol. 2006;154(3):498–504.
    View this article via: PubMed
  11. Terhorst D, Drecoll U, Stockfleth E, Ulrich C. Organ transplant recipients and skin cancer: assessment of risk factors with focus on sun exposure. Br J Dermatol. 2009;161(suppl 3):85–89.
    View this article via: PubMed CrossRef
  12. Varley JM. Germline TP53 mutations and Li-Fraumeni syndrome. Hum Mutat. 2003;21(3):313–320.
    View this article via: PubMed CrossRef
  13. Lapouge G, et al. Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci U S A. 2011;108(18):7431–7436.
    View this article via: PubMed CrossRef
  14. Caulin C, et al. An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations. J Clin Invest. 2007;117(7):1893–1901.
    View this article via: JCI.org PubMed CrossRef
  15. Flynn CM, Kaufman DS. Donor cell leukemia: insight into cancer stem cells and the stem cell niche. Blood. 2007;109(7):2688–2692.
    View this article via: PubMed
  16. Wong G, Chapman JR, Craig JC. Cancer screening in renal transplant recipients: what is the evidence? Clin J Am Soc Nephrol. 2008;3(suppl 2):S87–S100.
    View this article via: PubMed CrossRef
  17. Snyder TM, Khush KK, Valantine HA, Quake SR. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011;108(15):6229–6234.
    View this article via: PubMed CrossRef
  18. Iznerowicz A, et al. Duration of brain death and cold ischemia time, but not warm ischemia time, increases expression of genes associated with apoptosis in transplanted kidneys from deceased donors. Transplant Proc. 2011;43(8):2887–2890.
    View this article via: PubMed CrossRef
Advertisement
Advertisement