Applying molecular epidemiology in pediatric leukemia
=====================================================

* Joshua D Schiffman

## Abstract

Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members.

*   childhood leukemia
*   acute lymphoblastic leukemia
*   cancer predisposition
*   inherited cancer syndrome
*   genetic instability
*   DNA repair
*   inherited leukemia
*   familial leukemia
*   molecular epidemiology
*   genome wide association study

Molecular epidemiology is the study of the genetic and environmental causes of disease and both their interactions together to understand clinical risk, outcome, and prevention of disease. The field of molecular epidemiology has advanced rapidly with the introduction of the genomic era, especially in the field of cancer.1–3 Through many different types of genomic investigations, we have learned a tremendous amount about the molecular contribution to disease distribution. The field of molecular epidemiology continues to grow and adapt at a rapid pace while new sequencing technologies are introduced into studies. This has been especially true in childhood leukemia, where new advances in technology have allowed for the relatively recent identification of genetic risk factors for disease in both general population and high risk, inherited populations.

Childhood leukemia comprises nearly a third of all new cancer diagnoses in children and adolescents, making it one of the most common forms of pediatric cancer.4–6 Despite occurring so commonly, only a very small percentage of children diagnosed with leukemia are thought to be due to familial or hereditary cancer syndromes7; nevertheless, this small fraction of cases has proven very informative to our understanding of childhood cancer and even has impacted clinical management. In contrast to the single-gene, high penetrant familial disorders, many new studies being published describe the presence of recurring, low penetrant risk alleles or single nucleotide polymorphisms (SNPs) that may contribute to leukemia risk in children.8–10 The vast majority of childhood leukemia is acute lymphoblastic leukemia (ALL), which can be classified by immune cell phenotype as B-cell ALL (the most common) and T-cell ALL (less common and typically more aggressive). The other type of childhood leukemia includes acute myeloid leukemia (AML). As described later, each type of childhood leukemia can be associated with a different hereditary cancer syndrome, and sometimes a single syndrome can cause multiple leukemia subtypes. In addition to helping understand individual disease risk, along with possible clinical implications, the application of molecular epidemiology in leukemia helps shed light on the underlying biology of one of the most common childhood cancers.

## ALL Epidemiology

One of 2000 children will develop ALL, which translates to more than 3250 new cases of childhood acute leukemia diagnosed annually in the United States.11 ,12 Acute lymphoblastic leukemia is slightly more frequent in boys versus girls11 and in Hispanic and non-Hispanic whites versus African Americans,11 and most commonly presents in children between the ages of 2 to 6 years, the so called “common ALL.”4 ,6 ,11 Many theories exist to the causes of childhood leukemia, but no single unifying theory has yet been able to explain all cases. The general consensus now seems to point to a dysregulated immune response to infection as contributing to leukemia risk, due to either lack of infectious exposure, genetic impairment of response, or a combination of both of these factors. The population mixing hypothesis by Kinlen13 ,14 bases leukemia risk on exposure to demographic mixing and subsequent introduction of a viral infection to previously unexposed individuals in the perinatal period. The delayed infection hypothesis by Greaves15 ,16 describes leukemia risk due to delayed exposure to a common infection and an evolutionary mismatch between immune system exposure and modern, hygienic lifestyle. Fascinatingly, Greaves *et al.*17 have demonstrated preleukemic clones in dried newborn blood spots at birth, suggesting that the first preleukemic “hit” occurs before delayed infectious exposure. Greaves *et al.*18 also have described concordant ALL in identical (monozygotic) twins with shared identical translocation breakpoints, suggesting again that the first hit of ALL occurs in utero and, in the case of twins, the preleukemia clone has crossed across the placenta. Considering this molecular epidemiological evidence, an accepted model of ALL risk follows a combination of chance, exposure, and inherited genetic variation leading to in utero initiation followed by postnatal promotion and finally leukemia.4 As covered below, the process ofleukemia risk can be accelerated in the setting of hereditary cancer syndromes.

## Candidate Gene Approaches

Initially, while investigation began into the molecular epidemiology of childhood leukemia, one of the approaches was to explore specific “candidate genes” that could contribute to leukemia risk. Using technological approaches available at the time, study investigators most often looked at SNPs within single genes that were thought to be involved in the process of leukemia development and progression. When reviewing the hundreds of published studies available, the majority of these candidate genes associated with the biology of ALL can be divided into the following 5 main categories: (1) folate metabolism/transport, (2) xenobiotic metabolism/transport, (3) immune function, (4) DNA repair, and (5) cell cycle.9 ,10 Many of these studies have mixed and even conflicting results, demonstrating the difficulty in identifying risk genes for cancer. Nevertheless, several candidate genes seem to suggest an association with ALL risk and include *MTHFR* C677T (folate metabolism),19–27 *CYP1A1* TP235C (xenobiotic metabolism),28 ,29 *GSTM1* deletion (xenobiotic metabolism),29–34 NAT2*5 (xenobiotic metabolism),30 ,35–38 *XRCC1* G28152A (DNA repair),39 ,40 and HLA-DRB4 (encoding HLA-DR53 immune antigen).41–43

## Genome-Wide Association Studies

The introduction of SNP microarrays offered the possibility of studying hundreds of thousands, sometimes millions, of SNPs and their cancer risk in a simultaneously agnostic approach in what has become known as the genome-wide association study (GWAS). Several GWAS have been performed in the past few years on DNA from thousands of children diagnosed with leukemia. These GWAS have discovered SNPs within the following genes associated with growth regulation, hematopoiesis, and lymphocyte development: *IKZF1* (7p12.2), *CDKN2A* (9p21.3), *ARID5B* (10q21.2), and *CEBPE* (14q11.2) genes.44–49 These findings, seen in children from European descent, lead to almost a 3-fold risk for leukemia and are among the strongest cancer susceptibility variants identified through GWAS.50 In multiethnic populations (including African Americans and especially Hispanic Americans), other risk alleles have been identified, such as *ARID5B, CEBPE, BMI1-PIP4K2A* variants, and hyperdiploid subtype.51–53 Most recently, *GATA3* was identified through GWAS to be a risky allele for ALL diagnosed in adolescents and young adults.54 Although these GWAS findings probably account for less than 10% of genetic variation in ALL risk, they still suggest that genetic factors play a strong role in the development of childhood ALL.55

## Inherited Predisposition Syndromes

When discussing the leukemia-associated inherited cancer syndromes, it is helpful to divide these syndromes into the following 6 main categories based on biological functions and affected pathways: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes including pure familial leukemia. See Table 1 for the list of associated syndromes and genetic mutations for each category. For the purposes of this report, we will focus on the first category of genetic instability and DNA repair syndromes.

View this table:
[Table 1](/content/64/2/355/T1)

Table 1 
Leukemia predisposition and its associated hereditary cancer syndromes, modified from Malkin *et al.*8

## Genetic Instability/DNA Repair Syndromes

Although leukemia is typically not the primary malignancy often seen in these syndromes, it still plays an important role in cancer risk. Also, once diagnosed, individuals with these types of syndromes need to have treatment tailored to avoid excessive toxicity from their chemotherapy and radiation treatment. These syndromes offer an excellent example of how the application of molecular epidemiology in pediatric leukemia can impact patient care.

Li-Fraumeni syndrome (LFS) is due to *TP53* mutations and is associated with multiple cancer types including sarcomas, breast, and bone cancer.56 ,57 This is a highly penetrant cancer syndrome and occurs in the population at an estimated prevalence of 1/5000 to 1/20,000.58 ,59 Acute lymphoblastic leukemia, AML, and bone marrow myelodysplastic syndrome (MDS) have been reported, with hematological malignancies occurring about 1% to 3% of the time.59–62 Nearly half of patients with hypodiploid ALL might have germline *TP53* mutations,63 ,64 making it prudent to check for LFS in any patients diagnosed with hypodiploid ALL regardless of family history. Although leukemia surveillance is still being studied in LFS, some have recommended annual complete blood counts as part ofa biochemical screening program for early cancer detection.65

Biallelic mismatch repair syndrome is caused when two of the following mismatch DNA repair alleles are inherited: *MLH1*, *MSH2*, *MSH6*, and *PMS2*. Normally just associated with Lynch syndrome (hereditary nonpolyposis colon cancer),66 patients with biallelic (homozygous) alterations in the mismatch repair genes have multiple café-au-lait spots, pediatric brain tumors, and an especially high rate of pediatric hematological malignancies including both ALL and AML.67–71 The population prevalence of Lynch syndrome is high at 1/440;72 therefore, the biallelic mismatch repair syndrome would be estimated to be as low as 1/775,000. Any child presenting with leukemia who also has several café-au-lait spots and/or a family histoiy of colorectal cancer should be considered for testing for biallelic mismatch repair syndrome.

Fanconi anemia is often an autosomal recessive (AR) disorder of chromosomal breakage due to germline mutations in one of the 15 complementation groups, including *FANCA-C*, *FANCD1-2*, *FANCE-G*, *FANCI-J*, and *FANCL-P.*73 Typically, Fanconi anemia is diagnosed through a combination of bone marrow failure and its distinct physical characteristics including short stature, microcephaly, microphthalmia, epicanthal folds, dangling thumbs, ureteral defects, congenital dislocated hips, and rocker bottom feet.73 Fanconi anemia diagnosis can be complicated as up to 25% of affected individuals who do not display significant dysmorphology, and the disorder has high genetic het- erogeneity.73 Bone marrow failure often occurs between ages 5 to 15 years, 4 and just under 10% may develop AML or MDS.75 ,76 The cumulative probability of leukemia is nearly 40% by age 30 years, and MDS has a 50% cumulative incidence by age 50 years. Patients with Fanconi anemia remain very sensitive to DNA-damaging agents, especially radiation, and treatment often will be modified from standard care due to the high rate of secondary malignancy. Recommendation for surveillance for hematological malignancies in Fanconi anemia including measuring complete blood counts along annual bone marrow evaluation for changes in morphology, cellularity, and cytogenetics.73

Ataxia telangiectasia is caused by *ATM* mutations, and patients experience progressive ataxia with central nervous system degeneration, growth deficiency, ocular and facial telangiectasia, immunodeficiency, and a very high risk for hematological malignancies.77 ,78 Patients with *ATM* mutations experience a 70-fold increase in leukemia risk, mostly ALL.79 Due to an extreme sensitivity to ionizing radiation and risk for secondary malignancies, treating oncologists need to modify therapy accordingly. Despite the high risk for leukemia, no consensus on hematologic surveillance has been recommended for patients with Ataxia telangiectasia although patients should be aware of signs of malignancy including weight loss, bruising, and localized pain or swelling.78

Nimegen breakage syndrome is caused by germline mutations in the *NBS1* gene, responsible for DNA double-strand break repair in the same pathway as ATM80 with some of the same chromosomal breakage patterns seen in cells from patients with Ataxia telangiectasia.81 Patients with Nimegen breakage syndrome have distinctive dysmorpholgy, growth deficiency, immunodeficiency, cognitive impairment, and increased cancer risks approach 40% to 50%.77 ,82 ,83 Most frequently, patients with Nimegen breakage syndrome will develop lymphoma although a smaller percentage of individuals will develop ALL.83 Also similar to Ataxia telangiectasia, patients with Nimegen breakage syndrome need specifically tailored cancer treatment due to their extreme sensitivity to radiation and chemotherapy. Anyone found to have Nimegen breakage syndrome should be monitored for general signs of malignancy.82

*Bloom syndrome* is an AR disease due to *BLM* germline mutations, which is a helicase gene integral for double stranded DNA break repair.84 Bloom syndrome lymphocytes reveal a high frequency of characteristic sister chromatid exchanges and quadriradial configurations.85 ,86 Ashkenazi Jews carry the c.2207_2212delinsTAGATTC in *BLM* with an estimated carrier frequency of 1/100 due to a founder affect.77 ,85 With less than 300 cases reported, our knowledge about the natural history of this syndrome comes from the Bloom Syndrome Registry.87 Cancer is the most common cause of death, and patients have 25% cancer risk with multiple different tumor types developing at an early age of onset around 25 years.77 Twenty-one cases of acute leukemia were documented. Among the 168 registered patients with Bloom syndrome, 21 patients were documented acute leukemias (ALL, 6; AML, 6; biphenotypic, 2; and unspecified/other, 7).87 Similar to the other DNA repair syndromes described, patients with Bloom syndrome are sensitive to radiation and chemotherapy and therefore require specifically tailored treatment.85

In addition to the above syndromes related to genetic instability and DNA repair dysfunction, several other hereditary cancer syndromes have also been described with leukemia predisposition as either a major or minor component. As reported previously, many of these can be grouped into one of the following remaining categories: cell cycle/differentiation syndromes, bone marrow failure syndromes, telomere maintenance syndromes, immunodeficiency syndromes, and transcription factor syndromes with pure familial leukemia. A comprehensive description of these other syndromes with associated leukemia risk is beyond the scope of the current report, but the reader is directed to the 2 following reviews by Seif (2011)7 and Stieglitz and Loh (2013)88 for an excellent summary of leukemia predisposition. Understanding the genetic risk for childhood leukemia is very important to identify children, and their family members, who may be at risk for hereditary cancer predisposition.89 As discussed above, this has clear implications for treatment strategy and avoidance of therapy that may lead to secondary malignancies. In addition, if other family members are found to harbor the same genetic mutations, then they can be appropriately managed through early clinical screening and surveillance.90 In summary, molecular epidemiology has identified several important genetic causes of leukemia risk for both the general population and those with inherited cancer syndromes. Understanding this connection has increased our knowledge about the biology and development of leukemia, as well as provided important insight into the appropriate clinical management of these patients. While our genomic technologies continue to improve, even more information will be learned about leukemia predisposition and how to use this knowledge to impact the care of children and adults with acute leukemia.

## Footnotes

*   Funding Supported by the Edward B. Clark, MD, Chair in Pediatric Research and the Primary Children's Hospital Pediatric Cancer Program, funded by the Intermountain Healthcare Foundation and the Primary Children's Hospital Foundation.

*   Provenance and peer review Commissioned; internally peer reviewed.

## References

1.  Hartman M, Loy EY, Ku CS, et al. Molecular epidemiology and its current clinical use in cancer management. Lancet Oncol 2010;11:383–90.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S1470-2045(10)70005-X&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=20359664&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000276765100025&link_type=ISI) 

2.  Perera FP, Weinstein IB. Molecular epidemiology: recent advances and future directions. Carcinogenesis 2000;21:517–24.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FyY2luIjtzOjU6InJlc2lkIjtzOjg6IjIxLzMvNTE3IjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

3.  Vineis P, Perera F. Molecular epidemiology and biomarkers in etiologic cancer research: the new in light of the old. Cancer Epidemiol Biomarkers Prev 2007;16:1954–65.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czoxMDoiMTYvMTAvMTk1NCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

4.  Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet 2013;381:1943–55.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0140-6736(12)62187-4&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=23523389&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000320319500035&link_type=ISI) 

5.  Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact 2012;196:59–67.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/j.cbi.2012.01.007&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22326931&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

6.  Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med 2004;350:1535–48.
    
    [CrossRef](/lookup/external-ref?access_num=10.1056/NEJMra023001&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=15071128&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000220682000009&link_type=ISI) 

7.  Seif AE. Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet 2011;204:227–44.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/j.cancergen.2011.04.005&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=21665176&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

8.  Mullighan CG. The genomic landscape ofacute lymphoblastic leukemia in children and young adults. Hematology Am Soc Hematol Educ Program 2014;2014:174–80.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToiYmxvb2Rib29rIjtzOjU6InJlc2lkIjtzOjEwOiIyMDE0LzEvMTc0IjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

9.  Chokkalingam AP, Buffler PA. Genetic susceptibility to childhood leukaemia. Radiat Prot Dosimetry 2008;132:119–29.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoicnBkIjtzOjU6InJlc2lkIjtzOjk6IjEzMi8yLzExOSI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

10. Urayama KY, Chokkalingam AP, Manabe A, et al. Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia. Int J Hematol 2013;97:3–19.
    
    [PubMed](/lookup/external-ref?access_num=23239135&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

11. 1.  Ries L, 
    2.  Smith M, 
    3.  Gurney J, et al
    
    Smith M, Ries L, Gurney J, et al. Leukemia. In: Ries L, Smith M, Gurney J, et al., eds. Bethesda, MD: National Cancer Institute; 1999:17–35.
    
    

12. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992 2004). Cancer 2008;112:416–32.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/cncr.23169&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=18074355&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000252266200024&link_type=ISI) 

13. Kinlen L. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain. Lancet 1988;2:1323–27.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0140-6736(88)90867-7&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=2904050&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1988R273200001&link_type=ISI) 

14. Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 1995;71:1–5.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/bjc.1995.1&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=7819022&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1995QA57800001&link_type=ISI) 

15. Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer 2006;6:193–203.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/nrc1816&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16467884&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000235591900014&link_type=ISI) 

16. Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia 1988;2:120–5.
    
    [PubMed](/lookup/external-ref?access_num=3278171&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1988M185600010&link_type=ISI) 

17. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999;354:1499–503.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0140-6736(99)09403-9&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=10551495&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000083411300009&link_type=ISI) 

18. Greaves MF, Maia AT, Wiemels JL, et al. Leukemia in twins: lessons in natural history. Blood 2003;102:2321–33.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czoxMDoiMTAyLzcvMjMyMSI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

19. Wang H, Wang J, Zhao L, et al. Methylenetetrahydrofolate reductase polymorphisms and risk of acute lymphoblastic leukemia-evidence from an updated meta-analysis including 35 studies. BMC Med Genet 2012;13:77.
    
    [PubMed](/lookup/external-ref?access_num=22943282&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

20. Yan J, Yin M, Dreyer ZE, et al. A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2012;58:513–8.
    
    [PubMed](/lookup/external-ref?access_num=21495160&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

21. Goyal RK, Cooper JD. Meta-analyzing the link between MTHFR C677T genotype and susceptibility to childhood ALL. Pediatr Blood Cancer 2012;58:483–4.
    
    [PubMed](/lookup/external-ref?access_num=22180054&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

22. Zintzaras E, Doxani C, Rodopoulou P, et al. Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: a synthesis of genetic association studies. Cancer Epidemiol 2012;36:169–76.
    
    [PubMed](/lookup/external-ref?access_num=22094326&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

23. Metayer C, Scélo G, Chokkalingam AP, et al. Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control 2011;22:1243–58.
    
    [PubMed](/lookup/external-ref?access_num=21748308&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

24. Azhar MR, Rahimi Z, Vaisi-Raygani A, et al. Lack of association between MTHFR C677T and A1298C polymorphisms and risk of childhood acute lymphoblastic leukemia in the Kurdish population from Western Iran. Genet Test Mol Biomarkers 2012;16:198–202.
    
    [PubMed](/lookup/external-ref?access_num=22017305&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

25. Nikbakht M, MalekZadeh K, Kumar Jha A, et al. Polymorphisms of MTHFR and MTR genes are not related to susceptibility to childhood ALL in North India. Exp Oncol 2012;34:43–8.
    
    [PubMed](/lookup/external-ref?access_num=22453148&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

26. Lupo PJ, Nousome D, Kamdar KY, et al. A case-parent triad assessment of folate metabolic genes and the risk of childhood acute lymphoblastic leukemia. Cancer Causes Control 2012;23:1797–803.
    
    [PubMed](/lookup/external-ref?access_num=22941668&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

27. Amigou A, Rudant J, Orsi L, et al. Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE). Cancer Causes Control 2012;23:1265–77.
    
    [PubMed](/lookup/external-ref?access_num=22706675&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

28. Zhuo W, Zhang L, Qiu Z, et al. Does cytochrome P450 1A1 MspI polymorphism increase acute lymphoblastic leukemia risk? Evidence from 2013 cases and 2903 controls. Gene 2012;510:14–21.
    
    [PubMed](/lookup/external-ref?access_num=22964275&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

29. Vijayakrishnan J, Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica 2010;95:1405–14.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiaGFlbWF0b2wiO3M6NToicmVzaWQiO3M6OToiOTUvOC8xNDA1IjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

30. Chokkalingam AP, Metayer C, Scelo GA, et al. Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia. Cancer Causes Control 2012;23:1367–75.
    
    [CrossRef](/lookup/external-ref?access_num=10.1007/s10552-012-9947-4&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22674224&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

31. Chan JY, Ugrasena DG, Lum DW, et al. Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children. Hematol Oncol 2011;29:116–23.
    
    [PubMed](/lookup/external-ref?access_num=20824655&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

32. Yeoh AE, Lu Y, Chan JY, et al. Genetic susceptibility to childhood acute lymphoblastic leukemia shows protection in Malay boys: results from the Malaysia-Singapore ALL Study Group. LeukRes 2010;34:276–83.
    
    

33. Rimando MG, Chua MN, Yuson E, et al. Prevalence of GSTT1, GSTM1 and NQO1 (609C>T) in Filipino children with ALL (acute lymphoblastic leukaemia). Biosci Rep 2008;28:117–24.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InBwYmlvc2NpcmVwIjtzOjU6InJlc2lkIjtzOjg6IjI4LzMvMTE3IjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

34. Suneetha KJ, Nancy KN, Rajalekshmy KR, et al. Role of GSTM1 (Present/Null) and GSTP1 (Ile105Val) polymorphisms in susceptibility to acute lymphoblastic leukemia among the South Indian population. Asian Pac J Cancer Prev 2008;9:733–6.
    
    [PubMed](/lookup/external-ref?access_num=19256768&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

35. Krajinovic M, Richer C, Sinnett H, et al. Genetic polymorphisms of N-acetyltransferases 1 and 2 and gene-gene interaction in the susceptibility to childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev 2000;9:557–62.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo3OiI5LzYvNTU3IjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

36. Zanrosso CW, Emerenciano M, Faro A, et al. Genetic variability in N-acetyltransferase 2 gene determines susceptibility to childhood lymphoid or myeloid leukemia in Brazil. Leuk Lymphoma 2012;53:323–7.
    
    [PubMed](/lookup/external-ref?access_num=21888617&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

37. Silveira VS, Canalle R, Scrideli CA, et al. CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome. Mol Cell Biochem 2012;364(1-2):217–23.
    
    

38. Bonaventure A, Goujon-Bellec S, Rudant J, et al. Maternal smoking during pregnancy, genetic polymorphisms of metabolic enzymes, and childhood acute leukemia: the ESCALE study (SFCE). Cancer Causes Control 2012;23:329–45.
    
    [PubMed](/lookup/external-ref?access_num=22200898&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

39. Wang L, Yin F, Xu X, et al. X-ray repair cross-complementing group 1 (XRCC1) genetic polymorphisms and risk of childhood acute lymphoblastic leukemia: a meta-analysis. PLoS One 2012;7:e34897.
    
    

40. Wang R, Hu X, Zhou Y, et al. XRCC1 Arg399Gln and Arg194Trp polymorphisms in childhood acute lymphoblastic leukemia risk: a meta-analysis. Leuk Lymphoma 2013;54:153–9.
    
    [PubMed](/lookup/external-ref?access_num=22712837&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

41. Dorak MT, Oguz FS, Yalman N, et al. A male-specific increase in the HLA-DRB4 (DR53) frequency in high-risk and relapsed childhood ALL. Leuk Res 2002;26:651–6.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0145-2126(01)00189-8&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=12008082&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000178806500006&link_type=ISI) 

42. Dorak MT, Lawson T, Machulla HK, et al. Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia. Blood 1999;94:694–700.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czo4OiI5NC8yLzY5NCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

43. Taylor M, Hussain A, Urayama K, et al. The human major histocompatibility complex and childhood leukemia: an etiological hypothesis based on molecular mimicry. Blood Cells Mol Dis 2009;42:129–35.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/j.bcmd.2008.10.009&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19054700&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000263504300008&link_type=ISI) 

44. Ellinghaus E, Stanulla M, Richter G, et al. Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia. Leukemia 2012;26:902–9.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/leu.2011.302&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22076464&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000303883500006&link_type=ISI) 

45. Orsi L, Rudant J, Bonaventure A, et al. Genetic polymorphisms and childhood acute lymphoblastic leukemia: GWAS of the ESCALE study (SFCE). Leukemia 2012;26:2561–4.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/leu.2012.148&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22660188&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

46. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 2009;41:1006–10.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ng.430&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19684604&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000269382100013&link_type=ISI) 

47. Prasad RB, Hosking FJ, Vijayakrishnan J, et al. Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 2010;115:1765–7.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czoxMDoiMTE1LzkvMTc2NSI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

48. Sherborne AL, Hosking FJ, Prasad RB, et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat Genet 2010;42:492–4.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ng.585&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=20453839&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000278081500012&link_type=ISI) 

49. Trevino LR, Yang W, French D, et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 2009;41:1001–5.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ng.432&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19684603&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000269382100012&link_type=ISI) 

50. Fletcher O, Houlston RS. Architecture of inherited susceptibility to common cancer. Nat Rev Cancer 2010;10:353–61.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/nrc2840&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=20414203&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000276951300012&link_type=ISI) 

51. Xu H, Yang W, Perez-Andreu V, et al. Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst 2013;105:733–42.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5jaSI7czo1OiJyZXNpZCI7czoxMDoiMTA1LzEwLzczMyI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

52. Walsh KM, de Smith AJ, Chokkalingam AP, et al. Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype. Blood 2013;121:4808–9.
    
    [FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czoxMToiMTIxLzIzLzQ4MDgiO3M6NDoiYXRvbSI7czoxODoiL2ppbS82NC8yLzM1NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

53. Chokkalingam AP, Hsu LI, Metayer C, et al. Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics. Cancer Causes Control 2013;24:1789–95.
    
    [PubMed](/lookup/external-ref?access_num=23836053&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

54. Perez-Andreu V, Roberts KG, Xu H, et al. A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults. Blood 2015;125:680–6.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImJsb29kam91cm5hbCI7czo1OiJyZXNpZCI7czo5OiIxMjUvNC82ODAiO3M6NDoiYXRvbSI7czoxODoiL2ppbS82NC8yLzM1NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

55. Enciso-Mora V, Hosking FJ, Sheridan E, et al. Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 2012;26:2212–5.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/leu.2012.89&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22456626&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000309958300007&link_type=ISI) 

56. Li FP, Fraumeni JF Jr.. Soft-tissue sarcomas breast cancer other neoplasms. A familial syndrome? Ann Intern Med 1969;71:747–52.
    
    [CrossRef](/lookup/external-ref?access_num=10.7326/0003-4819-71-4-747&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=5360287&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1969E388700007&link_type=ISI) 

57. Malkin D, Li FP, Strong LC, et al. Germ Line p53 mutations in a familial syndrome ofbreast cancer, sarcomas, and other neoplasms. Science 1990;250:1233–8.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIyNTAvNDk4NS8xMjMzIjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

58. Lalloo F, Varley J, Ellis D, et al. Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. Lancet 2003;361:1101–2.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0140-6736(03)12856-5&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=12672316&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000181865200014&link_type=ISI) 

59. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:1250–6.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjk6IjI3LzgvMTI1MCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

60. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007;28:622–9.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/humu.20495&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17311302&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000246212800010&link_type=ISI) 

61. Ruijs MW, Verhoef S, Rookus MA, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet 2010;47:421–8.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToiam1lZGdlbmV0IjtzOjU6InJlc2lkIjtzOjg6IjQ3LzYvNDIxIjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

62. Kleihues P, Schäuble B, zur Hausen A, et al. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 1997;150:1–3.
    
    [PubMed](/lookup/external-ref?access_num=9006316&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1997WB76100001&link_type=ISI) 

63. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242–52.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ng.2532&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=23334668&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

64. Powell BC, Jiang L, Muzny DM, et al. Identification ofTP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing. Pediatr Blood Cancer 2012;60:E1–E3.
    
    [PubMed](/lookup/external-ref?access_num=23255406&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

65. Villani A, Tabori U, Schiiìman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12:559–67.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S1470-2045(11)70119-X&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=21601526&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000291842400019&link_type=ISI) 

66. 1.  Pagon RA, 
    2.  Rick TD, 
    3.  Dolan CR et al
    
    Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, Rick TD, Dolan CR et al., eds. GeneReviews Seattle: University of Washington; 1993–2005.
    
    

67. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 2008;124:105–22.
    
    [CrossRef](/lookup/external-ref?access_num=10.1007/s00439-008-0542-4&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=18709565&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000258759300001&link_type=ISI) 

68. Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair. Clin Genet 2007;71:483–98.
    
    [CrossRef](/lookup/external-ref?access_num=10.1111/j.1399-0004.2007.00803.x&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17539897&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000246918000001&link_type=ISI) 

69. Scott RH, Mansour S, Pritchard-Jones K, et al. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol 2007;4:130–4.
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ncponc0719&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17259933&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000243790500014&link_type=ISI) 

70. Ripperger T, Beger C, Rahner N, et al. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma report on a novel biallelic MSH6 mutation. Haematologica 2010;95:841–4.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiaGFlbWF0b2wiO3M6NToicmVzaWQiO3M6ODoiOTUvNS84NDEiO3M6NDoiYXRvbSI7czoxODoiL2ppbS82NC8yLzM1NS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

71. Bandipalliam P. Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer 2005;4:323–33.
    
    [CrossRef](/lookup/external-ref?access_num=10.1007/s10689-005-8351-6&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16341812&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000235351800011&link_type=ISI) 

72. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479–87.
    
    [CrossRef](/lookup/external-ref?access_num=10.1001/jama.296.12.1479&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17003396&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000240770000024&link_type=ISI) 

73. 1.  Pagon RA, 
    2.  Adam MP, 
    3.  Ardinger HH, et al
    
    Alter BP, Kupfer G. Fanconi anemia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews Seattle, WA: University of Washington; 1993–2005.
    
    

74. Soulier J, Fanconi anemia. Hematology Am Soc Hematol Educ Program 2011;2011:492–7.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToiYmxvb2Rib29rIjtzOjU6InJlc2lkIjtzOjEwOiIyMDExLzEvNDkyIjtzOjQ6ImF0b20iO3M6MTg6Ii9qaW0vNjQvMi8zNTUuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

75. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003;97:425–40.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/cncr.11046&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=12518367&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000180401600011&link_type=ISI) 

76. Alter BP, Greene MH, Velazquez I, et al. Cancer in Fanconi anemia. Blood 2003;101:2072.
    
    

77. Jones KL, Smith DW. Smith 's Recognizable Patterns of Human Malformation 6th ed. Philadelphia: Elsevier Saunders; 2006.
    
    

78. 1.  Pagon RA, 
    2.  Adam MP, 
    3.  Ardinger HH, et al
    
    Gatti R. Ataxia-telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews Seattle, WA: University of Washington; 1993–2015.
    
    

79. Liberzon E, Avigad S, Stark B, et al. Germ-line ATM gene alterations are associated with susceptibility to sporadic T-cell acute lymphoblastic leukemia in children. Genes Chromosomes Cancer 2004;39:161–6.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/gcc.10306&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=14695997&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000187851500009&link_type=ISI) 

80. Varon R, Reis A, Henze G, et al. Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res 2001;61:3570–2.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FucmVzIjtzOjU6InJlc2lkIjtzOjk6IjYxLzkvMzU3MCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

81. Kleier S, Herrmann M, Wittwer B, et al. Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome. Clin Genet 2000;57:384–7.
    
    [PubMed](/lookup/external-ref?access_num=10852373&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

82. 1.  Pagon RA, 
    2.  Bird TD, 
    3.  Dolan CR, et al
    
    Concannon P, Gatti R, Nijmegen breakage syndrome. In: Pagon RA, Bird TD, Dolan CR, et al., eds. GeneReviews Seattle Wash: University of Washington; 1993–2015.
    
    

83. Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000;82:400–6.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImFyY2hkaXNjaGlsZCI7czo1OiJyZXNpZCI7czo4OiI4Mi81LzQwMCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

84. Popp HD, Bohlander SK. Genetic instability in inherited and sporadic leukemias. Genes Chromosomes Cancer 2010;49:1071–81.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/gcc.20823&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=20842730&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 

85. 1.  Pagon RA, 
    2.  Adam MP, 
    3.  Ardinger HH, et al
    
    Sanz MM, German J, Bloom's syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews Seattle, WA: University of Washington; 1993–2015.
    
    

86. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the *BLM* gene in persons in the Bloom's Syndrome Registry. Hum Mutat 2007;28:743–53.
    
    [CrossRef](/lookup/external-ref?access_num=10.1002/humu.20501&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17407155&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000248748300001&link_type=ISI) 

87. German J, Bloom's syndrome XX. The first 100 cancers. Cancer Genet Cytogenet 1997;93:100–6.
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0165-4608(96)00336-6&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=9062585&link_type=MED&atom=%2Fjim%2F64%2F2%2F355.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1997WL24500013&link_type=ISI) 

88. Stieglitz E, Loh ML. Genetic predispositions to childhood leukemia. Ther Adv Hematol 2013;4:270–90.
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3B0YWgiO3M6NToicmVzaWQiO3M6NzoiNC80LzI3MCI7czo0OiJhdG9tIjtzOjE4OiIvamltLzY0LzIvMzU1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

89. Malkin D, Nichols KE, Zelley K, et al. Predisposition to pediatric and hematologic cancers: a moving target. Am Soc Clin Oncol Educ Book 2014:e44–e55.
    
    

90. Knapke S, Zelley K, Nichols KE, et al. Identification, management, and evaluation of children with cancer-predisposition syndromes. Am Soc Clin Oncol Educ Book 2012:576–84.