Acute myeloid leukaemia associated with Muir-Torre variant of hereditary non-polyposis colon cancer (HNPCC): implications for inherited and acquired mutations in DNA mismatch repair genes


Hereditary non-polyposis colon cancer (HNPCC) is the most prevalent familial colon cancer syndrome. It is characterized by multiple colonic as well as extra colonic tumours, such as ovarian, endometrial and urinary tract cancers and is caused by germline mutations in DNA mismatch repair (MMR) genes, especially the MSH2 and MLH1 genes (Syngal, 2000). The ‘Muir-Torre’ variant of HNPCC is defined by the additional development of sebaceous tumours, such as sebaceous adenoma, epithelioma or carcinoma (Coldron & Reid, 2001; Bandipalliam, 2005). Acute myeloid leukaemia (AML) is not considered to be involved in the spectrum of diseases related to HNPCC. However, the acquired loss of MMR genes has recently been reported in AML (Mao et al, 2008). In this respect, we report a unique case of treatment-resistant AML in a patient with Muir-Torre variant of HNPCC.

The patient initially presented in 1996 aged 38 years with a colonic carcinoma and was treated with a right hemicolectomy and adjuvant 5-Flourouracil (5-FU) chemotherapy. The patient had a strong family history of bowel and uterine cancer leading to confirmation of HNPCC with a heterozygous mutation in the MSH2 gene, and subsequent screening of the patient and family members. In 2000, at the age of 42 years, he developed liver metastases and underwent partial hepatectomy and thereafter has continued to be in complete remission of the colonic cancer with routine on-going surveillance.

In September 2004, at the age of 46 years, the patient presented with AML with chromosomal translocation t(6;9), which is not a known association with therapy-related AML (Kayser et al, 2011). He was treated with standard intensive chemotherapy and achieved complete remission (CR) after cycle 1 of daunorubicin and cytarabine (DA), and then received consolidation chemotherapy with DA and MACE (mitoxantrone, cytrabine, etoposide). The patient remained well until February 2007 when relapse of AML was confirmed on bone marrow examination with cytogenetic evolution to a complex karyotype – 46, XY,-2,-5,der(5)ins(5;?)(q1?1;?),t(6;9) (p23;q34),add(8)(q1),der(12)t(2;12)(p1;p1),add(17)(p1), der (17)t(2;17)(q1;q11),der(21)t(5;21)(q1?1;q22),+mar[19]. DEK/NUP214 (previously termed DEK/CAN) gene rearrangement was detectable by florescence in situ hybridization (FISH). MSH2 gene mutation status was not checked in leukaemic cells as it is a constitutional mutation and bound to be present in all cells. He received salvage chemotherapy with fludarabine, cytarabine and idarubicin (FLAG-Ida regimen). Second complete remission was achieved but the treatment was complicated by prolonged cytopenia requiring autologous bone marrow rescue and a fungal pneumonia treated with systemic anti-fungal drugs and surgical resection. Based on high risk of further relapse with chemotherapy alone, the patient underwent matched unrelated donor allogeneic peripheral blood stem cell transplantation (SCT) following reduced intensity conditioning with fludarabine 30 mg/m2 × 5 days, melphalan 140 mg/m2 and alemtuzumab 10 mg × 5 days in July 2008. There was prompt engraftment (neutrophil count > 0·5 × 109/l on day +12, platelet count > 20 × 109/l on day +14) with no graft-versus-host disease.

In September 2009 a lesion removed from the conjunctival aspect of his right lower eye-lid was histologically confirmed as in situ sebaceous adenocarcinoma, consistent with the ‘Muir-Torre’ variant of HNPCC. More recently, in May 2011 he presented with a new eye lesion, which was removed and confirmed to be in situ sebaceous adenocarcinoma. At the time of writing in July 2011, the AML continues to be in remission (almost 3 years post-transplant). Figure 1 demonstrates the timeline of the various cancers in our patient.

Figure 1.

 Timeline of various cancers in our patient.

Mutations in mismatch repair MMR genes are highly recognized in the development of solid cancers, but their importance in haematological malignancies is less well understood. A recent study showed that acquired mutation and loss of function of MMR genes could play a role in the development of de novo AML in association with MSH2 and MLH1 mutations (Mao et al, 2008). Loss of MMR genes was higher in relapsed and refractory AML, and mutated MMR genes were also associated with resistance to chemotherapeutic agents (Scott et al, 2007; Mao et al, 2008). Despite this, reports of leukaemia and/or lymphoma in patients with inherited mutations of the MMR genes are limited to one series. All patients had a homozygous or compound heterozygous mutation of MMR genes and the mean age at presentation of leukaemia and/or lymphoma was 5·6 years, with carcinomas developing later in life (Bandipalliam, 2005).

Our patient differed in that he developed colonic carcinoma and AML in the fourth and fifth decade of life, respectively. Whether the AML was de novo or related to previous chemotherapy treatment for the colonic carcinoma is unclear even though presence of complex karyotype favours a hypothesis of therapy-related AML. It is also not clear if this condition predisposes to the development of AML with complex karyotype as the data is limited. However pyrimidine anti-metabolites, such as 5-FU, are rarely associated with the development of leukaemia (Abe et al, 2000). In addition, the subsequent development of sebaceous adenocarcinoma, a feature of HPNCC ‘Muir-Torre’ variant may well have been accelerated by an interaction of the inherited MSH2 mutation and allogeneic SCT, as the latter is a well-known risk factor for the development of secondary cancers (Lowsky et al, 1994).

The unique circumstances of this case provide further support for inherited or acquired MSH2 mutations and defective DNA mismatch repair predisposing to development of AML. Although no recommendations can be made on the basis of a single patient, a degree of caution in exposing HNPCC patients to the potentially mutagenic effects of chemotherapy and irradiation may be reasonable, and screening of full blood count for cytopenia and dysplastic changes would be an inexpensive and reasonable addition alongside other routine long-term surveillance measures of HNPCC patients. The treatment-resistant AML associated with the inherited heterozygous MSH2 gene mutation in our case concurs with the observations of AML with acquired mutations (Scott et al, 2007; Mao et al, 2008), and the good response to allogeneic SCT is notable. We encourage reporting of further cases of AML and haematological malignancies in these rare HPNCC families.


We are thankful to RE Walker for valuable contribution in the preparation of this manuscript and P Talley for providing the data on cytogenetics and FISH.