High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.
Hematopoietic cell transplantation (HCT) is now a curative option for certain categories of patients with hematological malignancies and other life-threatening illnesses. Technical and supportive care has resulted in survival rates that exceed 70% for those who survive the first two years after HSCT. However, long-term survivors carry a high burden of morbidity, including endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies. Understanding the etiologic pathways that lead to specific post-HCT morbidities is critical to developing targeted prevention and intervention strategies. Understanding the molecular underpinnings associated with graft vs. host disease (GvHD), organ toxicity, relapse, opportunistic infection and other long-term complications now recognized as health care concerns will have significant impact on translational research aimed at developing novel targeted therapies for controlling chronic GvHD, facilitating tolerance and immune reconstitution, reducing risk of relapse and secondary malignancies, minimizing chronic metabolic disorders and improving quality of life. However, several methodological challenges exist in achieving these goals; these issues are discussed in detail in this article.
We describe 70 children with myelodysplastic syndrome [refractory cytopenia (n=31) and refractory anemia with excess blasts (n=30) or blasts in transformation (n=9)] who received umbilical cord blood (UCB) transplantation with a single UCB unit and a myeloablative conditioning regimen. Approximately 20% of children had secondary myelodysplastic syndrome. Median age at transplantation was 7 years and the median follow-up, 3 years. The day-60 probability of neutrophil recovery was 76%; recovery was faster after transplantation of matched or 1-locus mismatched UCB, irradiation-containing conditioning regimen, cell dose >6 × 107/kg and monosomy 7. Risks of treatment failure (recurrent disease or death) were lower in patients with monosomy 7 and transplantations after 2001. The 3-year disease-free survival (DFS) was 50% for transplantations after 2001 compared to 27% for the earlier period (p=0.018). Transplantations after 2001 occurred within 6 months after diagnosis and used UCB units with higher cell dose. DFS was highest in patients with monosomy 7 (61%) compared to other karyotypes (30%), p=0.017. These data suggest transplantation of mismatched UCB graft is an acceptable alternative for children without a matched sibling or suitably matched unrelated adult donor.
myelodysplastic syndrome; cord blood transplantation; monosomy 7
We describe long-term disease-free survival after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55, refractory anemia with excess blasts (RAEB) and 17, refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, p=0.002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, p=0.01) or RAEB-t (RR 11.00, p=0.004). Treatment failure (recurrent disease or death from any cause; inverse of disease-free survival [DFS]) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, p=0.001) and in those with RAEB-t (RR 2.38, p=0.02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy and children with RC can be expected to have the best outcome.
pediatric myelodysplastic syndrome; unrelated donor; bone marrow transplantation
Hematopoietic cell transplantation is an elective procedure that results in prolonged immune suppression and high treatment-related morbidity and mortality. Transplant centers and physicians use a variety of prophylaxis and monitoring strategies to prevent or minimize complications. Little is known about the variability in these practices. We conducted an international Internet-based survey of 526 physicians to describe the spectrum of supportive care practices employed. Consistency in pretransplant cardiac (96%) and pulmonary (95%) screening, informed consent documentation (93%), and use of antifungal prophylaxis (92%) was observed. Greater heterogeneity was seen in use of myelogenous growth factors, empiric antibiotic therapy, protective isolation procedures, posttransplant monitoring, and environmental and social restrictions. Although some practice differences were associated with physician characteristics and transplant type, most practice variation remained unexplained. These results suggest a need for well-designed observational and interventional studies to provide data about which supportive care practices improve outcomes. For practices proved to be beneficial, publication of guidelines and incorporation of monitoring into quality improvement initiatives may help standardize practices.
Practice variation; Supportive care; Autologous stem cell transplantation; Allogeneic stem cell transplantation
The aim of this study was to identify risk factors associated with progression-free survival in patients with Ewing sarcoma undergoing autologous stem cell transplantation (ASCT); 116 patients underwent ASCT in 1989-2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of progression-free survival in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30 – 69) and 34% (95% CI 22 – 47) respectively. The 5-year probability of progression-free survival in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3 – 30). Progression-free survival rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.
Autologous transplant; Ewing sarcoma; Progression-free survival
The variant polymorphism in the gene MDM2, SNP309, leads to increased level of mdm2 protein and subsequent downregulation of p53 tumor suppressor pathway. Presence of this single nucleotide polymorphism (SNP) has been associated with earlier tumorigenesis in patients with Li-Fraumeni syndrome, as well as decreased survival in patients with CLL. In addition, cells homozygous (G/G) for SNP 309 were found to have ten fold increase resistance to topoisomerase II inhibitors in vitro.
We genotyped children (n=575) with de novo acute myeloid leukemia (AML) treated on three Children’s Oncology Group protocols (CCG 2941/2961/AAML 03P1) for the presence of SNP309. Healthy blood donors were genotyped as control population.
The variant G/G genotype was associated with an increased susceptibility to AML (OR 1.5; p=0.049). However, the presence of the variant allele at SNP309 did not modify disease response or toxicity in children treated on CCG protocols 2941/2961.
The variant SNP 309 influences susceptibility to pediatric AML, but does not impact overall response to therapy.
AML; MDM2; SNP 309; Children’s Oncology Group; susceptibility
Leukemia in infants is rare and has not been well-studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants vs. older children suggest a distinct etiology, likely involving prenatal factors.
We examined the association between eight categories of maternally-reported congenital abnormalities (CAs) (cleft lip or palate, spina bifida or other spinal defect, large or multiple birthmarks, other chromosomal abnormalities, small head or microcephaly, rib abnormalities, urogenital abnormalities, and other) and infant leukemia in a case-control study. The study included 443 cases diagnosed at <1 year of age at a Children’s Oncology Group institution in the United States or Canada from 1996-2006 and 324 controls. Controls were recruited from the cases’ geographic area either by random digit dialing (1999-2002) or through birth certificates (2003-2008) and were frequency-matched to cases on birth year. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjustment for birth year and a measure of follow-up time to account for differences in the CA observation period.
No statistically significant associations were observed between infant leukemia and any CA (OR=1.2; 95% CI 0.8-1.9), birthmarks (OR=1.4, 95% CI 0.7-2.5), urogenital abnormalities (OR=0.7; 95% CI 0.2-2.0), or other CA (OR=1.4; 95% CI 0.7-2.8). Results were similar for acute lymphoblastic and myeloid leukemia cases. Fewer than five subjects were in the remaining CA categories precluding analysis.
Overall, we did not find evidence to support an association between CAs and infant leukemia.
infant leukemia; risk factors; congenital abnormalities; birth defects
Analysis of biological samples in large cohort studies may provide insight into the mechanism of, and risk factors for, disease onset and progression.
This study describes the methods used to collect biological samples from a large multi-center cohort of childhood cancer survivors and siblings of childhood cancer survivors, and evaluates the predictors of a positive response among these individuals.
Among survivors, female sex, white race/ethnicity, college graduation, never smoking, accessing the health care system in the past two years, and having a second malignant neoplasm were the strongest predictors of returning a sample. Among siblings, a similar demographic profile defined those likely to submit the requested sample.
To reduce selection bias and increase the value of these samples for future analysis, additional phone calls and reminders targeting non-responders are needed to improve response rates among those least likely to respond to a single mailed request.
neoplasm; pediatric; buccal mucosa; cohort study; DNA
Private cord blood banks are for-profit companies that facilitate storage of umbilical cord blood for personal or family use. Pediatric hematopoietic cell transplantation (HCT) physicians are currently best situated to use cord blood therapeutically. We sought to describe the experiences and views of these physicians regarding private cord blood banking.
Participants and Methods
Emailed cross-sectional survey of pediatric HCT physicians in the United States and Canada. 93/152 potentially eligible physicians (93/130 confirmed survey recipients) from 57 centers responded. Questions addressed the number of transplants performed using privately banked cord blood, willingness to use banked autologous cord blood in specific clinical settings, and recommendations to parents regarding private cord blood banking.
Respondents reported having performed 9 autologous and 41 allogeneic transplants using privately banked cord blood. In 36/40 allogeneic cases for which data were available, the cord blood had been collected because of a known indication in the recipient. Few respondents would choose autologous cord blood over alternative stem cell sources for treatment of acute lymphoblastic leukemia in second remission. In contrast, 55% would choose autologous cord blood to treat high-risk neuroblastoma, or to treat severe aplastic anemia in the absence of an available sibling donor. No respondent would recommend private cord blood banking for a newborn with one healthy sibling when both parents were of Northern European descent; 11% would recommend banking when parents were of different minority ethnicities.
Few transplants have been performed using cord blood stored in the absence of a known indication in the recipient. Willingness to use banked autologous cord blood varies depending on disease and availability of alternative stem cell sources. Few pediatric HCT physicians endorse private cord blood banking in the absence of an identified recipient, even for mixed-ethnicity children for whom finding a suitably matched unrelated donor may be difficult.
Hematopoietic Stem Cell Transplantation; Cord Blood Stem Cell Transplantation; Bioethics
Cytosine arabinoside (ara-C) is irreversibly deaminated by cytidine deaminase (CDD) to a nontoxic metabolite. A common polymorphism, A79C, in CDD changes a lysine residue to glutamine resulting in decreased enzyme activity. We determined CDD A79C genotypes for 457 children with AML treated on CCG 2941 and 2961 and analyzed the impact of CDD genotype on therapy outcomes. Post-Induction treatment related mortality (TRM) was significantly elevated in children with the CC genotype (5 year TRM 17 ± 13% CC vs 7 ± 4% AA, 5 ± 4% AC, p= 0.05). This was more notable in children who received IDA-FLAG (ara-C= 7590 mg/m2) (5 year TRM 24 ± 21% CC vs 6 ± 6% AA, 6 ± 7% AC, p=0.07) as consolidation therapy compared to IDA-DCTER (ara-C= 800 mg/m2) (5 year TRM 15 ± 20% CC vs 8 ± 6% AA, 4 ± 6% AC; p=0.29). Relapse-free survival was non-significantly increased in children with the CC genotype treated with IDA-FLAG (76 ± 20% CC vs 59 ± 12% AA and 55 ± 14% AC; p= 0.40). These data indicate that children with a low activity CDD genotype are at increased risk of treatment-related mortality with Ara-C based therapy for AML.
We examined the role of hematopoietic cell transplantation (HSCT) for patients aged ≤18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (n=52) and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92 – 43 matched sibling and 49 unrelated donor) HSCT in 1990–2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, marrow stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for diffuse large B cell (50% vs. 52%), Burkitt (31% vs. 27%) and anaplastic large cell lymphoma (46% vs. 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs. 4%, p<0.01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histologic sub-types.
Non-Hodgkin lymphoma; allogeneic HSCT; autologous HSCT
Success of hematopoietic-cell transplantation (HCT) can vary by race, but the impact of socioeconomic-status (SES) is not known. To evaluate the role of race and SES, we studied 6207 unrelated-donor myeloablative HCT recipients transplanted between 1995–2004 for acute or chronic leukemia or myelodysplastic syndrome. Patients were reported by transplant center to be White (n=5253), African-American (n=368), Asian/Pacific-Islander (n=141), or Hispanic (n=445). Patient income was estimated from residential ZIP Code at time of HCT. Cox-regression analysis adjusting for other significant factors showed that African-American (but not Asian or Hispanic) recipients had worse overall survival (OS) (relative-risk [RR] 1.47 (95% CI 1.29–1.68), P<0.001) compared to Whites. Treatment-related mortality (TRM) was higher in African-Americans (RR 1.56, (1.34–1.83), P<0.001) and in Hispanics (RR 1.30, (1.11–1.51), P=0.001). Across all racial groups, patients with median incomes in the lowest quartile (<$34,700) had worse OS (RR 1.15 (1.04–1.26), P=0.005) and higher risks of TRM (RR 1.21 (1.07–1.36), P=0.002). Inferior outcomes among African-Americans are not fully explained by transplant-related factors or SES. Potential other mechanisms such as genetic polymorphisms that impact drug metabolism or unmeasured co-morbidities, socioeconomic factors and health behaviors may be important. Low SES, regardless of race, has a negative impact on unrelated donor HCT outcomes.
Allogeneic hematopoietic cell transplantation; unrelated donor; race; socioeconomic status; survival
Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups.
Patients and Methods
We evaluated whether imatinib (340 mg/m2/d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Ph+ ALL (N = 92) and compared toxicities to Ph− ALL patients (N = 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n = 7) to 280 continuous days (cohort 5; n = 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) –identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT.
Continuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% ± 11% (95% CI, 64% to 90%), more than twice historical controls (35% ± 4%; P < .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% ± 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% ± 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction.
Imatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Ph+ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.
Interleukin-1 alpha (IL-1α) is a pro-inflammatory cytokine that is implicated in the initiation/maintenance of graft-versus-host disease (GVHD) and the immune response to infection. A cytosine (C) to thymine (T) transition at position −889 is believed to influence gene transcription. A previous single institution study showed that the presence of at least one IL1A T allele in the donor was associated with improved survival after unrelated donor haematopoietic stem cell transplant and lower transplant-related mortality if the donor and recipient each possessed the IL1A T allele. The present study sought to confirm these results in a larger homogeneous population. Thus the study population included 426 patients older than 18 years with chronic myeloid leukaemia (CML), transplanted in first chronic phase and receiving a total body irradiation and cyclophosphamide preparative regimen. Donor recipient pairs were categorised into four groups according to the presence or absence of an IL1A T allele in the donor and recipient. There were no significant differences in patient, donor and transplant characteristics between the groups. We did not observe an association with IL-1α genotype in donor and/or recipient and transplant-outcome. These data suggest that the outcome of unrelated donor transplant for CML is not influenced by IL-1α genotype.
interleukin-1; polymorphisms; chronic myeloid leukaemia; unrelated donor; haematopoietic stem cell transplantation
Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.
FAS is a cell surface receptor involved in apoptotic signal transmission. Deregulation of this pathway results in down regulation of apoptosis and subsequent persistence of a malignant clone. A single nucleotide polymorphism resulting in guanine-to-adenine (G→A) transition in the FAS promoter region (position –1377) is thought to reduce stimulatory protein 1 (SP1) transcription factor binding and decrease FAS expression. Previous work has shown increased risk of developing acute myeloid leukemia (AML) in adult patients with a variant allele at this site. The same authors have shown that the presence of an adenine residue rather than a guanine residue at –1377 bp significantly attenuates transcription factor SP1 binding and may contribute to a reduction in FAS expression and ultimately to the enrichment of apoptosis-resistant clones in AML. We hypothesized that FAS genotype by altering susceptibility to apoptosis might impact outcome of childhood AML therapy.
440 children treated for de novo AML on a uniform protocol were genotyped for FAS 1377.
There were no significant differences in overall survival (OS), event-free survival (EFS), treatment-related mortality (TRM), or relapse rate between patients with FAS 1377GG genotype vs. 1377GA/1377AA genotypes.
FAS1377 genotype does not alter outcome of de novo AML in children.
Identify prognostic factors that influence outcome after unrelated donor bone marrow transplantation in children with acute myeloid leukemia (AML).
Patients and Methods
Included are 268 patients (age ≤ 18 years) with AML in second complete remission (n = 142), relapse (n = 90), or primary induction failure (n = 36) at transplantation. All patients received bone marrow grafts from an unrelated donor and a myeloablative conditioning regimen. Cox regression models were constructed to identify risk factors that influence outcome after transplantation.
In this analysis, the only risk factor that predicted leukemia recurrence and overall and leukemia-free survival was disease status at transplantation. The 5-year probabilities of leukemia-free survival were 45%, 20%, and 12% for patients who underwent transplantation at second complete remission, relapse, and primary induction failure, respectively. As expected, risk of acute but not chronic graft-versus-host disease (GVHD) was lower with T-cell–depleted bone marrow grafts; T-cell–depleted grafts were not associated with higher risks of leukemia recurrence. We observed similar risks of leukemia relapse in patients with and without acute and chronic GVHD.
Children who underwent transplantation in remission had a superior outcome compared with children who underwent transplantation during relapse or persistent disease. Nevertheless, 20% of children who underwent transplantation in relapse are long-term survivors, suggesting that unrelated donor bone marrow transplantation is an effective therapy in a significant proportion of children with recurrent or primary refractory AML.
We retrospectively compared clinical outcomes in 1593 T-repleted URD marrow transplant recipients with AML, MDS and CML who received myeloablative conditioning regimens of either busulfan and cyclophosphamide (BuCy), standard-dose Cy/TBI (1,000-1,260 cGy) or high-dose Cy/TBI (1,320-1,500 cGy). Subjects were drawn from patients transplanted between 1991 and 1999 facilitated by the National Marrow Donor Program (NMDP). Patients who received high-dose Cy/TBI regimens were slightly younger, more likely to receive a mismatched transplant and to have intermediate or advanced disease compared to patients in the BuCy or standard-dose TBI group. Neutrophil recovery was significantly higher in the standard dose CY/TBI group compared to the high-dose Cy/TBI or BuCy group. Patients who received the high-dose Cy/TBI regimen had an increased risk of developing grade III-IV aGVHD when compared to the control group who received BuCy (p=0.011). Overall survival (OS), disease free survival (DFS), transplant-related mortality (TRM) and relapse were not significantly different between any of the regimens. We conclude that BuCy, standard-dose and high dose Cy/TBI regimens have equivalent efficacy profiles for OS, DFS, TRM and relapse risk in patients undergoing T-replete URD marrow transplantation for AML, CML and MDS.
Unrelated donor transplantation; TBI conditioning regimens; Busulfan
Reduced intensity conditioning (RIC) regimens have been used extensively in adults with hematological malignancies. To address whether this is a feasible approach for children with acute lymphoblastic leukemia (ALL), we evaluated transplant outcomes in 38 recipients transplanted from 1995–2005 for whom this was their first transplant. The median age at transplant was 12 years and 47% had performance scores <90%. Disease status was first complete remission (CR) in 13%, ≥CR2 in 60% of patients and 22% had active disease at transplantation. Matched related donors were available for a third of patients and about half of whom received bone marrow (BM) and the others, peripheral blood progenitor cells (PBPC). Sixty percent of unrelated donor transplant recipients received PBPC. The day-100 probability of grade 2–4 acute GVHD was 37% and the 3-year probability of chronic GVHD, 26%. At 3-years, the probability of transplant related mortality was 40%, relapse, 37% and disease-free survival (DFS), 30%. These data indicate long-term DFS can be achieved using RIC regimens in children with ALL. Given the relatively small cohort, these findings must be validated in a larger population.
pediatric; ALL; reduced intensity conditioning
Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response.
Using a genome-wide approach, to assess the contribution of inherited genetic variation to therapy response and to identify germline single nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy.
Design, Setting, and Patients
We performed a genome-wide interrogation of 476,796 germline SNPs to identify genotypes that predicted MRD in two independent cohorts of children with newly diagnosed ALL: 318 patients on St. Jude trials Total XIIIB and XV and 169 patients on a Children’s Oncology Group (COG) trial P9906.
Main Outcome Measures
MRD at the end of induction therapy, measured by flow cytometry.
There were 102 SNPs associated with MRD in both cohorts (P≤0.0125), including 5 SNPs in the interleukin 15 (IL15) gene. A high proportion, 21 of these 102 SNPs, also predicted hematologic relapse (P<0.05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were also associated with early response, relapse, or with drug disposition.
Host genetic variability affected treatment response for childhood ALL, and germline variants may exert their effects on MRD by effects on leukemic cell biology and on host disposition of antileukemic drugs.