Skip to main content

Advertisement

SpringerLink
Log in

Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting

  • Original Article
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Patients with mismatch repair (MMR) deficient colorectal cancer (CRC) without detectable germline pathogenic variants (PVs) or likely pathogenic variants (LPVs) in MMR genes are often labeled as Lynch-like syndrome (LLS). We sought to evaluate the efficacy of paired tumor and germline testing in risk stratification of patients with LLS in a large, community-based, integrated healthcare setting. Through the universal screening program for Lynch syndrome at Kaiser Permanente Northern California, we identified all patients with MMR deficient colorectal tumors without detectable germline PVs or LPVs between April 2011 and October 2018. These patients were categorized as LLS and were offered paired tumor and germline testing. Risk stratification and patient management were assessed upon completion of all testing. Of the 50 patients with LLS who underwent paired tumor and germline testing, 62% (n = 31) were categorized as sporadic, 6% (n = 3) had Lynch syndrome, and 32% (n = 16) remained inconclusive. Among the sporadic cases, 65% (n = 20) had a PV (n = 18) or LPV (n = 2) in combination with loss of heterozygosity while 35% (n = 11) had two somatic PVs/LPVs involving the same MMR gene. Our findings showed paired tumor and germline testing resolved the etiology in the majority of patients and is a valuable strategy in risk stratification and management of patients with LLS. Further studies are needed to assess the optimal application of paired testing in different practice settings, particularly with evolving technology and decreasing cost of molecular sequencing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Data was collected from the database of Genetics Department, Kaiser Permanente, San Jose and is available from the corresponding author [H.C.] on request.

Abbreviations

CRC:

Colorectal cancer

IHC:

Immunohistochemistry

KPNC:

Kaiser Permanente Northern California

MMR:

Mismatch repair

dMMR:

Mismatch repair deficiency

LLS:

Lynch-like syndrome

PV:

Pathogenic variant

LPV:

Likely pathogenic variant

LOH:

Loss of heterozygosity

VUS:

Variant of uncertain significance

References

  1. Ladabaum U, Ford JM, Martel M et al (2015) American gastroenterological association technical review on the diagnosis and management of Lynch syndrome. Gastroenterology 149(3):783–813

    Article  Google Scholar 

  2. Jarvinen HJ, Aarnio M, Mustonen H et al (2000) Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118(5):829–834

    Article  CAS  Google Scholar 

  3. Watson P, Lynch H (2001) Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1:57–60

    Article  CAS  Google Scholar 

  4. Watson P, Vasen HF, Mecklin JP et al (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123(2):444–449

    Article  CAS  Google Scholar 

  5. Schmeler KM, Lynch HT, Chen LM et al (2006) Prophylactic surgery to reduce the risk of gynecological cancers in the Lynch syndrome. N Engl J Med 354(3):261–269

    Article  CAS  Google Scholar 

  6. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN GuidelinesTM) (2019) Genetic/familial high-risk assessment: colorectal (version 2.2019). National Comprehensive Cancer Network, Inc. www.nccn.org

  7. Li D, Hoodfar E, Jiang SF, Udaltsova N et al (2019) Comparison of universal versus age-restricted screening of colorectal tumors for Lynch syndrome using mismatch repair immunohistochemistry: a cohort study. Ann Intern Med 171(1):19–26

    Article  Google Scholar 

  8. Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26(35):5783–5788

    Article  Google Scholar 

  9. Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860

    Article  CAS  Google Scholar 

  10. Ladabaum U (2020) What is Lynch-like syndrome and how should we manage it? Clin Gastroenterol Hepatol 18(2):294–296

    Article  Google Scholar 

  11. Boland CR (2013) The mystery of mismatch repair deficiency: Lynch or Lynch-like? Gastroenterology 144(5):868–870

    Article  Google Scholar 

  12. Lynch HT, Boland CR, Rodriguez-Bigas MA et al (2007) Who should be sent for genetic testing in hereditary colorectal cancer syndromes? J Clin Oncol 25:3534–3542

    Article  Google Scholar 

  13. Rodriguez-Soler M, Perez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected Lynch syndrome without germline mutation. Gastroenterology 144:926–932

    Article  CAS  Google Scholar 

  14. Porkka N, Lahtinen L, Ahtiainen M et al (2019) Epidemiological, clinical and molecular characterization of Lynch-like syndrome: a population-based study. Int J Cancer 145(1):87–98

    Article  CAS  Google Scholar 

  15. Geurts-Giele WR, Lennen CH, Dubbink HJ et al (2014) Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers. J Pathol 234(4):548–559

    Article  CAS  Google Scholar 

  16. Haraldsdottir S, Hampel H, Tomsic J et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic rather than germline mutations. Gastroenterology 147(6):1308–1316

    Article  Google Scholar 

  17. Mesenkamp AR, Vogelaar IP, van Zelst-Stams WA et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch -repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146(3):643–646

    Article  Google Scholar 

  18. Pearlman R, Haraldsdottir S, de la Chapelle A et al (2019) Clinical characteristics of colorectal cancer patients with double somatic mismatch repair mutations compared to Lynch syndrome. J Med Genet 56(7):462–470

    Article  CAS  Google Scholar 

  19. Gordon NP (2015) Similarity of the Adult Kaiser Permanente Membership in Northern California to the Insured and General Population in Northern California: Statistics from the 2011 California Health Interview Survey. Kaiser Permanente Northern California Division of Research, Oakland

    Google Scholar 

  20. Gray PN, Tsai P, Chen D et al (2018) TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome. Oncotarget 9(29):20304–20322

    Article  Google Scholar 

  21. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424

    Article  Google Scholar 

  22. Salvador MU, Truelson MRF, Mason C et al (2019) Comprehensive paired tumor/germline testing for Lynch syndrome: bringing resolution to the diagnostic process. J Clin Oncol 37(8):647–657

    Article  CAS  Google Scholar 

  23. Picó MD, Castillejo A, Murcia Ó et al (2020) Clinical and pathological characterization of Lynch-like syndrome. Clin Gastroenterol Hepatol 18:368–374

    Article  Google Scholar 

  24. Jansen AML, Goel A (2020) Mosaicism in patients with colorectal cancer or polyposis syndromes: a systematic review. Clin Gastroenterol Hepatol 18(9):1949–1960

    Article  CAS  Google Scholar 

  25. Friedman E, Efrat N, Soussan-Gutman L et al (2015) Low-level constitutional mosaicism of a de novoBRCA1 gene mutation. Br J Cancer 112(4):765–768

    Article  CAS  Google Scholar 

  26. Alhopuro P, Vainionpää R, Anttonen AK et al (2020) Constitutional mosaicism for a BRCA2 mutation as a cause of early-onset breast cancer. Fam Cancer 19(4):307–310

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We greatly appreciate the assistance from Sheng-Fang Jiang, MS, Division of Research, Kaiser Permanente Northern California, Oakland, CA for conducting statistical analysis.

Funding

Kaiser Permanente Northern California Genetics Department funding for H.C, E.H. and J.B. The Permanente Medical Group Delivery Science and Applied Research Program and the Physician Researcher Program funding for D.L.

Author information

Authors and Affiliations

  1. Department of Genetics, Kaiser Permanente Northern California, 5755 Cottle Road, Building 21, San Jose, CA, 95123, USA

    Holly Carwana & JoAnn Bergoffen

  2. Department of Genetics, Kaiser Permanente Northern California, Roseville, CA, USA

    Elizabeth Hoodfar

  3. Department of Gastroenterology, Kaiser Permanente Northern California, Santa Clara, CA, USA

    Dan Li

  4. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    Dan Li

Authors
  1. Holly Carwana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth Hoodfar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. JoAnn Bergoffen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HC: study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. EH: study concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; acquisition of data. JB: study concept and design; critical revision of the manuscript for important intellectual content; study supervision. DL: drafting of the manuscript, critical revision of the manuscript for important intellectual content; study supervision.

Corresponding author

Correspondence to Holly Carwana.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 28 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carwana, H., Hoodfar, E., Bergoffen, J. et al. Efficacy of paired tumor and germline testing in evaluation of patients with Lynch-like syndrome in a large integrated healthcare setting. Familial Cancer 20, 223–230 (2021). https://doi.org/10.1007/s10689-020-00218-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-020-00218-w

Keywords

Search

Navigation