lunes, 3 de noviembre de 2014

Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair-deficient tumors : Genetics in Medicine : Nature Publishing Group

Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair-deficient tumors : Genetics in Medicine : Nature Publishing Group



Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair–deficient tumors

Genetics in Medicine
 
(2014)
 
doi:10.1038/gim.2014.131
Received
 
Accepted
 
Published online 

Abstract

Purpose:

Mismatch repair-deficient (MMRD) colorectal cancer (CRC) and endometrial cancer (EC) may be suggestive of Lynch syndrome (LS). LS can be confirmed only by positive germ-line testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germ-line−) have LS. Because LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germ-line− CRC and/or EC patients with LS CRC and/or EC patients.

Methods:

A total of 253 individuals with an MMRD CRC or EC from one institution were included for analysis in one of four groups: LS; MMRD+/germ-line−; MMRD tumor with variant of uncertain significance (MMRD+/VUS); and sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation orBRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM1,2,6. Kruskal–Wallis tests were used to compare family history scores.

Results:

MMRD+/germ-line− individuals had significantly lower median family history scores (MMRpro = 8.1, PREMM1,2,6 = 7.3) than did LS individuals (MMRpro = 89.8, PREMM1,2,6 = 26.1, P < 0.0001).

Conclusion:

MMRD+/germ-line− individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germ-line− individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.
Genet Med advance online publication 23 October 2014
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Keywords:

 
genetic testing; Lynch syndrome; mismatch repair–deficient tumor; tumor studies

References

  1. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology1993;104:1535–1549.
  2. Ponti G, Losi L, Pedroni M, et al. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas. J Invest Dermatol 2006;126:2302–2307.
  3. South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst2008;100:277–281.
  4. Watson P, Vasen HF, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008;123:444–449.
  5. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet2009;75:141–149.
  6. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 2009;11:35–41.
  7. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788.
  8. Fishel R, Kolodner RD. Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev 1995;5:382–395.
  9. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3’ exons of TACSTD1. Nat Genet 2009;41:112–117.
  10. Moreira L, Balaguer F, Lindor N, et al.; EPICOLON Consortium. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308:1555–1565.
  11. Heald B, Plesec T, Liu X, et al. Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol 2013;31:1336–1340.
  12. Morak M, Koehler U, Schackert HK, et al.; German HNPCC consortium. Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. J Med Genet 2011;48:513–519.
  13. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;187:330–337.
  14. Sourrouille I, Coulet F, Lefevre JH, et al. Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 2013;12:27–33.
  15. Mesenkamp AR, Vogelaar IP, van Zelst-Sstams WAG, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch Syndrome-like tumors. Gastroenterology 2014;146:643–646.
  16. Chen S, Wang W, Lee S, et al.; Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006;296:1479–1487.
  17. Howlander N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). 2012. http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed 1 March 2012.
  18. Stoffel E, Mukherjee B, Raymond VM, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 2009;137:1621–1627.
  19. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology2013;144:926–932.e1; quiz e13.
  20. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology2011;140:73–81.
  21. Buchanan DD, Tan YY, Walsh MD, et al. Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing. J Clin Oncol 2014;32:90–100.
  22. Rahner N, Friedrichs N, Steinke V, et al. Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome. J Pathol 2008;214:10–16.
  23. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer2009;48:737–744.
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Author information

Affiliations

  1. Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Katherine M. Dempsey,
      •  
    • Maureen Mork,
      •  
    • Molly Daniels &
      •  
    • Karen Lu

  2. Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Katherine M. Dempsey &
      •  
    • Molly Daniels

  3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

    • Katherine M. Dempsey,
      •  
    • Russell Broaddus,
      •  
    • Sarah Jane Noblin,
      •  
    • Molly Daniels &
      •  
    • Karen Lu

  4. Department of Pathology Administration, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Russell Broaddus

  5. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Y. Nancy You &
      •  
    • Maureen Mork

  6. Department of Obstetrics and Gynecology, The University of Texas Health Science Center at Houston, Houston, Texas, USA

    • Sarah Jane Noblin

  7. Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, Texas, USA

    • Sarah Jane Noblin &
      •  
    • Molly Daniels

  8. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    • Bryan Fellman &
      •  
    • Diana Urbauer

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