Abstract
Clinicians involved in cancer treatment often utilize somatic tumor sequencing to
help tailor chemotherapy and immunotherapy. However, somatic tumor sequencing can
also identify patients at risk for germline pathogenic variants causing cancer predisposition
syndromes like Lynch syndrome. The extent to which clinicians realize this implication
of tumor sequencing is currently unclear. We performed a retrospective chart review
of Stanford Health Care patients who had somatic variant(s) in the Lynch syndrome
genes or microsatellite instability identified on tumor sequencing to determine the
proportion of patients who were referred to genetics. Among 6,556 patients who had
tumor testing, 90 (1.37%) had findings compatible with Lynch syndrome. Of the 62 patients
who had not already seen genetics, 47/62 (75.8%) were not referred to genetics for
germline testing. Additionally, 26/47 (55.3%) of these individuals had a tumor type
within the Lynch syndrome spectrum. Of the 10 patients who did elect germline testing
after tumor sequencing, 3/10 were positive for Lynch syndrome. Our study highlights
the need for specific guidelines to inform clinician referral practices on germline
follow-up of somatic tumor testing and demonstrates the importance of continued research
on the relationship between somatic tumor variants and germline variants to inform
such guidelines.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Cancer GeneticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Precision oncology: who, how, what, when, and when not?.Am Soc Clin Oncol Educ B. 2017; : 160-169https://doi.org/10.1200/edbk_174176
- The rise of the genome and personalised medicine.Clin Med J R Coll Physicians London. 2017; 17: 545-551https://doi.org/10.7861/clinmedicine.17-6-545
- Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat Med. 2017; 23: 703-713https://doi.org/10.1038/nm.4333
- Germline and Somatic Tumor Testing in Gynecologic Cancer Care.Obstet Gynecol Clin North Am. 2019; 46: 37-53https://doi.org/10.1016/j.ogc.2018.09.003
- Determining if a somatic tumor mutation is targetable and options for accessing targeted therapies.J Oncol Pract. 2019; 15: 575-583https://doi.org/10.1200/jop.19.00262
- Final common pathway’ of human cancer immunotherapy: Targeting random somatic mutations.Nat Immunol. 2017; 18: 255-262https://doi.org/10.1038/ni.3682
- Germline and somatic mutations in prostate cancer: focus on defective DNA repair, PARP inhibitors and immunotherapy.Futur Oncol. 2020; 16: 75-80https://doi.org/10.2217/fon-2019-0745
- Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American society of clinical oncology, and college of American pathologists.J Mol Diagn. 2017; 19: 4-23https://doi.org/10.1016/j.jmoldx.2016.10.002
- Germline findings in tumor-only sequencing: points to consider for clinicians and laboratories.J Natl Cancer Inst. 2016; 108: djv351https://doi.org/10.1093/jnci/djv351
- The emerging significance of secondary germline testing in cancer genomics.J Pathol. 2018; 244: 610-615https://doi.org/10.1002/path.5031
- Germline Testing for Patients with BRCA1/2 Mutations on Somatic Tumor Testing.JNCI Cancer Spectr. 2019; 4: 4pkz095https://doi.org/10.1093/jncics/pkz095
- Germline variants in targeted tumor sequencing using matched normal DNA.JAMA Oncol. 2016; 2: 104https://doi.org/10.1001/jamaoncol.2015.5208
- NCCN clinical practice guidelines in oncology genetic/familial high-risk assessment: colorectal.2021 ([cited 2021 Aug 30]Available from)
- Prevalence and penetrance of major genes and polygenes for colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2017; 26: 404-412https://doi.org/10.1158/1055-9965.EPI-16-0693
- Importance of PCR-based tumor testing in the evaluation of lynch syndrome-associated endometrial cancer.Adv Anat Pathol. 2017; 24: 372-378https://doi.org/10.1097/PAP.0000000000000169
- A practice guideline from the American college of medical genetics and genomics and the national society of genetic counselors: referral indications for cancer predisposition assessment.Genet Med. 2015; 17: 70-87https://doi.org/10.1038/gim.2014.147
- Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.Cancer. 2018; 124: 3145-3153https://doi.org/10.1002/cncr.31534
- Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome.Hum Pathol. 2017; 70: 121-128https://doi.org/10.1016/j.humpath.2017.10.022
- Universal screening for mismatch-repair deficiency in endometrial cancers to identify patients with lynch syndrome and lynch-like syndrome.Int J Gynecol Pathol. 2017; 36: 115-127https://doi.org/10.1097/PGP.0000000000000312
- Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis.Ann Intern Med. 2011; 155 (10.7326/0003-4819-155-2-201107190-00002.): 69-79
- PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520https://doi.org/10.1056/NEJMoa1500596
- R: A language and environment for statistical computing.R Foundation for Statistical Computing, Vienna, Austria2020 (URL)
- Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer.J Clin Oncol. 2019; 37: 286-295https://doi.org/10.1200/JCO.18.00283
- Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas.J Mol Diagn. 2009; 11: 238-247https://doi.org/10.2353/jmoldx.2009.080142
Article Info
Publication History
Published online: March 05, 2022
Accepted:
February 28,
2022
Received in revised form:
February 18,
2022
Received:
September 28,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
