Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Management of familial cancer: sequencing, surveillance and society


The clinical management of familial cancer begins with recognition of patterns of cancer occurrence suggestive of genetic susceptibility in a proband or pedigree, to enable subsequent investigation of the underlying DNA mutations. In this regard, next-generation sequencing of DNA continues to transform cancer diagnostics, by enabling screening for cancer-susceptibility genes in the context of known and emerging familial cancer syndromes. Increasingly, not only are candidate cancer genes sequenced, but also entire 'healthy' genomes are mapped in children with cancer and their family members. Although large-scale genomic analysis is considered intrinsic to the success of cancer research and discovery, a number of accompanying ethical and technical issues must be addressed before this approach can be adopted widely in personalized therapy. In this Perspectives article, we describe our views on how the emergence of new sequencing technologies and cancer surveillance strategies is altering the framework for the clinical management of hereditary cancer. Genetic counselling and disclosure issues are discussed, and strategies for approaching ethical dilemmas are proposed.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Evolution of clinical genetic screening for hereditary cancers.


  1. 1

    Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11, 685–696 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Schiffman, J. D. et al. Update on pediatric cancer predisposition syndromes. Pediatr. Blood Cancer 60, 1247–1252 (2013).

    Article  Google Scholar 

  3. 3

    Bakry, D. et al. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur. J. Cancer 50, 987–996 (2014).

    Article  Google Scholar 

  4. 4

    Vasen, H. F. et al. Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). J. Med. Genet. 51, 283–293 (2014).

    CAS  Article  Google Scholar 

  5. 5

    Hill, D. A. et al. DICER1 mutations in familial pleuropulmonary blastoma. Science 325, 965 (2009).

    CAS  Article  Google Scholar 

  6. 6

    Choong, C. S., Priest, J. R. & Foulkes, W. D. Exploring the endocrine manifestations of DICER1 mutations. Trends Mol. Med. 18, 503–505 (2012).

    CAS  Article  Google Scholar 

  7. 7

    de Kock, L. et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol. 128, 583–595 (2014).

    CAS  Article  Google Scholar 

  8. 8

    Rothenberg, S. M. & Settleman, J. Discovering tumor suppressor genes through genome wide copy number analysis. Curr. Genomics 5, 297–310 (2010).

    Article  Google Scholar 

  9. 9

    Costa, J. L., Meijer, G., Ylstra, B. & Caldas, C. Array comparative genomic hybridization copy number profiling: a new tool for translational research in solid malignancies. Semin. Radiat. Oncol. 18, 98–104 (2008).

    Article  Google Scholar 

  10. 10

    Comino-Mendez, I. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat. Genet. 43, 663–667 (2011).

    CAS  Article  Google Scholar 

  11. 11

    Smith, M. J. et al. Loss of function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat. Genet. 45, 295–298 (2013).

    CAS  Article  Google Scholar 

  12. 12

    Shah, S. et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat. Genet. 45, 1226–1231 (2013).

    CAS  Article  Google Scholar 

  13. 13

    Stadler, Z. K., Schrader, K. A., Vijai, J., Robson, M. E. & Offit, K. Cancer genomics and inherited risk. J. Clin. Oncol. 32, 687–698 (2014).

    CAS  Article  Google Scholar 

  14. 14

    Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome—biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Lawlor, E. R. & Theiele, C. J. Epigenetic changes in pediatric solid tumors: promising new targets. Clin. Cancer Res. 18, 2768–2779 (2012).

    CAS  Article  Google Scholar 

  16. 16

    Killian, J. K. et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648–657 (2013).

    CAS  Article  Google Scholar 

  17. 17

    Choufani, S., Shuman, C. & Weksberg, R. Molecular findings in Beckwith–Wiedemann syndrome. Am. J. Med. Genet. C. Sem. Med. Genet. 163C, 131–140 (2013).

    Article  Google Scholar 

  18. 18

    Mardis, E. R. Next-generation sequencing platforms. Annu. Rev. Anal. Chem. (Palo Alto Calif.) 6, 287–303 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Idris, S. F., Ahmad, S. S., Scott, M. A., Vassiliou, G. S. & Hadfield, J. The role of high-throughput technologies in clinical cancer genomics. Expert Rev. Mol. Diagn. 13, 167–181 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014).

    CAS  Article  Google Scholar 

  21. 21

    Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31, 55–59 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Hu, H. et al. A unified test of linkage analysis and rare variant association for analysis of pedigree sequence data. Nat. Biotechnol. 32, 663–669 (2014).

    CAS  Article  Google Scholar 

  23. 23

    Gartner, J. J. et al. Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma. Proc. Natl Acad. Sci. USA 110, 13481–13486 (2013).

    CAS  Article  Google Scholar 

  24. 24

    Ward, L. D. & Kellis, M. Interpreting noncoding genetic variation in complex human traits and human disease. Nat. Biotechnol. 30, 1095–1106 (2012).

    CAS  Article  Google Scholar 

  25. 25

    Turnbull, C. et al. Gene–gene interactions in breast cancer susceptibility. Hum. Mol. Genet. 21, 958–962 (2012).

    CAS  Article  Google Scholar 

  26. 26

    Moorman, P. G. et al. Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis. Breast Cancer Res. Treat. 124, 441–451 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Samuel, N. & Hudson, T. J. Translating genomics to the clinic: implications of cancer heterogeneity. Clin. Chem. 59, 127–137 (2013).

    CAS  Article  Google Scholar 

  28. 28

    Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Scott, R. H. et al. Stratification of Wilms tumor by genetic and epigenetic analysis. Oncotarget 3, 327–335 (2012).

    Article  Google Scholar 

  30. 30

    Behjati, S. et al. A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing. PLoS ONE 9, e96531 (2014).

    Article  Google Scholar 

  31. 31

    Stein, L. D. An introduction to the informatics of “next-generation” sequencing. Curr. Protoc. Bioinformatics 11, 11.1 (2011).

    Google Scholar 

  32. 32

    Biesecker, L. G., Burke, W., Kohane, I., Plon, S. E. & Zimmern, R. Next-generation sequencing in the clinic: are we ready? Nat. Rev. Genet. 13, 818–824 (2012).

    CAS  Article  Google Scholar 

  33. 33

    Knapke, S., Nagarajan, R., Correll, J., Kent, D. & Burns, K. Hereditary cancer risk assessment in a pediatric oncology follow-up clinic. Pediatr. Blood Cancer 58, 85–89 (2012).

    Article  Google Scholar 

  34. 34

    Fernandez, C. V. et al. Attitudes of parents to the return of targeted and incidental genomic research findings in children. Genet. Med. 16, 633–640 (2014).

    Article  Google Scholar 

  35. 35

    Ross, L. F., Saal, H. M., David, K. L., Anderson, R. R. & American Academy of Pediatrics; American College of Medical Genetics and Genomics. Technical report: ethical and policy issues in genetic testing and screening of children. Genet. Med. 15, 234–245 (2013).

    Article  Google Scholar 

  36. 36

    Fabsitz, R. B. et al. Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ. Cardiovasc. Genet. 3, 574–580 (2010).

    Article  Google Scholar 

  37. 37

    Wolf, S. M. Return of individual research results and incidental findings: facing the challenges of translational science. Annu. Rev. Genomics Hum. Genet. 14, 557–577 (2013).

    CAS  Article  Google Scholar 

  38. 38

    Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 15, 565–574 (2013).

    CAS  Article  Google Scholar 

  39. 39

    American College of Medical Genetics and Genomics. ACMG Updates Recommendation on “Opt Out” for Genome Sequencing Return of Results [online], (2014).

  40. 40

    McGuire, A. L. et al. Point–counterpoint. Ethics and genomic incidental findings. Science 340, 1047–1048 (2013).

    CAS  Article  Google Scholar 

  41. 41

    Holm, I. A. et al. Guidelines for return of research results from pediatric genomic studies: deliberations of the Boston Children's Hospital Gene Partnership Informed Cohort Oversight Board. Genet. Med. 16, 547–552 (2014).

    Article  Google Scholar 

  42. 42

    Clayton, E. W. et al. Addressing the ethical challenges in genetic testing and sequencing of children. Am. J. Bioeth. 14, 3–9 (2014).

    Article  Google Scholar 

  43. 43

    Eckstein, L., Garrett, J. R. & Berkman, B. E. A framework for analyzing the ethics of disclosing genetic research findings. J. Law Med. Ethics 42, 190–207 (2014).

    Article  Google Scholar 

  44. 44

    Fernandez, C. V. et al. Attitudes of Canadian researchers toward the return to participants of incidental and targeted genomic findings obtained in a pediatric research setting. Genet. Med. 15, 2558–2564 (2013).

    Article  Google Scholar 

  45. 45

    Rasmussen, A. et al. Uptake of genetic testing and long-term surveillance in von Hippel–Lindau disease. BMC Med. Genet. 11, 4 (2010).

    Article  Google Scholar 

  46. 46

    Barrow, P., Khan, M., Lalloo, F., Evans, D. G. & Hill, J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br. J. Surg. 100, 1719–1731 (2013).

    CAS  Article  Google Scholar 

  47. 47

    Brandi, M. L. et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 86, 5658–5671 (2001).

    CAS  Article  Google Scholar 

  48. 48

    Ramirez-Ortiz, M. A. et al. Diagnostic delay and sociodemographic predictors of stage at diagnosis and mortality in unilateral and bilateral retinoblastoma. Cancer Epidemiol. Biomarkers Prev. 23, 784–792 (2014).

    Article  Google Scholar 

  49. 49

    Green, D. The evolution of treatment of Wilms tumor. J. Pediatr. Surg. 48, 14–19 (2013).

    Article  Google Scholar 

  50. 50

    Ward, E., DeSantis, C., Robbins, A., Kohler, B. & Jemal, A. Childhood and adolescent cancer statistics, 2014. CA Cancer J. Clin. 64, 83–103 (2014).

    Article  Google Scholar 

  51. 51

    Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: a prospective observational study. Lancet Oncol. 12, 559–567 (2011).

    CAS  Article  Google Scholar 

  52. 52

    Broniscer, A. et al. Clinial and molecular characteristics of malignant transformation of low-grade glioma in children. J. Clin. Oncol. 25, 682–689 (2007).

    CAS  Article  Google Scholar 

  53. 53

    Jasperson, K. W. et al. Role of rapid sequence whole-body MRI screening in SDH-associated hereditary paraganglioma families. Fam. Cancer 13, 257–265 (2014).

    CAS  Article  Google Scholar 

  54. 54

    Choyke, P. L., Siegel, M. J., Craft, A. W., Green, D. M. & DeBaun, M. R. Screening for Wilms tumor in children with Beckwith–Wiedemann syndrome or idiopathic hemihypertrophy. Med. Pediatr. Oncol. 32, 196–200 (1999).

    CAS  Article  Google Scholar 

  55. 55

    Lammens, C. R. et al. Regular surveillance for Li–Fraumeni syndrome: advice, adherence and perceived benefits. Fam. Cancer 9, 647–654 (2010).

    CAS  Article  Google Scholar 

  56. 56

    Rothschild, P. R. et al. Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study. Eye (Lond.) 25, 1555–1561 (2011).

    Article  Google Scholar 

  57. 57

    Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: stratégie thérapeutique du rétinoblastome guide clinique canadien. Can. J. Ophthalmol. 44 (Suppl. 2), S1–S88 (2009).

  58. 58

    Imhof, S. M., Moll, A. C., Schouten-van Meeteren, A. Y. Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands. Br. J. Ophthalmol. 90, 875–878 (2006).

    CAS  Article  Google Scholar 

  59. 59

    Cairns, S. R. et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut 59, 666–689 (2010).

    Article  Google Scholar 

  60. 60

    Tan, T. Y. & Amor, D. J. Tumour surveillance in Beckwith–Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J. Paediatr. Child Health 42, 486–490 (2006).

    Article  Google Scholar 

  61. 61

    McNeil, D. E., Brown, M., Ching, A. & DeBaun, M. R. Screening for Wilms tumor and hepatoblastoma in children with Beckwith–Wiedemann syndromes: a cost-effective model. Med. Pediatr. Oncol. 37, 349–356 (2001).

    CAS  Article  Google Scholar 

  62. 62

    Clericuzio, C. L. et al. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith–Wiedemann syndrome or isolated hemihyperplasia. J. Pediatr. 143, 270–272 (2003).

    Article  Google Scholar 

  63. 63

    Poulsen, M. L., Budtz-Jørgensen, E. & Bisgaard, M. L. Surveillance in von Hippel–Lindau disease (vHL). Clin. Genet. 77, 49–59 (2010).

    CAS  Article  Google Scholar 

  64. 64

    Listernick, R., Ferner, R. E., Liu, G. T. & Gutmann, D. H. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann. Neurol. 61, 189–198 (2007).

    CAS  Article  Google Scholar 

  65. 65

    Bree, A. F., Shah, M. R. & BCNS Colloquium Group. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am. J. Med. Genet. A 155A, 2091–2097 (2011).

    Article  Google Scholar 

  66. 66

    Evans, D. G. et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br. J. Neurosurg. 19, 5–12 (2005).

    CAS  Article  Google Scholar 

  67. 67

    Krueger, D. A., Northrup, H. & International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol. 49, 255–265 (2013).

    Article  Google Scholar 

  68. 68

    Geller, J. I., Leslie, N. D. & Yin, H. Malignant Rhabdoid Tumor Follow-up [online], (2012).

    Google Scholar 

  69. 69

    Schultz, K. A. et al. Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma. Pediatr. Blood Cancer 61, 1695–1697 (2014).

    Article  Google Scholar 

  70. 70

    Doros, L. et al. DICER1-realted disorders (eds Pagon, R. A. et al.) in GeneReviews® [internet] (University of Washington; 2014).

    Google Scholar 

Download references


The work of the authors is supported in part by grants from the Canadian Institutes of Health Research (CIHR) to D.M. Both N.S. and A.V. receive salary support through scholarships from CIHR.

Author information




All authors made substantial contributions to each stage of the preparation of the manuscript for submission. N.S. and A.V. contributed equally to the manuscript.

Corresponding author

Correspondence to David Malkin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Samuel, N., Villani, A., Fernandez, C. et al. Management of familial cancer: sequencing, surveillance and society. Nat Rev Clin Oncol 11, 723–731 (2014).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing