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Comparison of universal screening in major lynch-associated tumors: a systematic review of literature

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Abstract

Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74–56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54–23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61–12.19%], OC [11.29% (320/2833), 95% CI 10.13–12.47%] and UT [11.2% (31/276), 95% CI 7.48–14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03–24.57], followed by EC [2.6% (97/3765), 95% CI 2.09–3.11], CRC [1.8% (682/37,220), 95% CI 1.66–1.94%], UT [1.8%(3/164), 95% CI − 0.24–3.83%] and OC [0.83%(25/2983), 95% CI 0.48–1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60–18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93–5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.

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Abbreviations

LS:

Lynch syndrome

CRC:

Colorectal cancer

EC:

Endometrial cancer

OC:

Ovarian cancer

UT:

Uterine cancer

ST:

Sebaceous tumors

MSI:

Microsatellite instability

IHC:

Immunohistochemistry

MMR:

Mismatch repair

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Funding

Supported by NIH Grant P50CA62924.

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Authors and Affiliations

  1. Clinical Assistant Professor, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 511 Idlewild Ave, Easton, MD, 21601, USA

    George Kunnackal John

  2. Pulmonary and Critical Care Fellow, Allegheny Health Network, Pittsburgh, PA, 15212, USA

    Vipin Das Villgran

  3. Medical Librarian, Johns Hopkins Bayview Medical Center, Baltimore, MD, 21224, USA

    Christine Caufield-Noll

  4. Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Francis M. Giardiello

Authors
  1. George Kunnackal John
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  2. Vipin Das Villgran
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  3. Christine Caufield-Noll
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  4. Francis M. Giardiello
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Contributions

GKJ and FG were responsible for study concept. GKJ and CCN designed search strategy. GKJ and VV were responsible for screening manuscripts and extracting data. GKJ performed statistical analysis. All authors were involved in critical revision of the manuscript.

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Correspondence to George Kunnackal John.

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Kunnackal John, G., Das Villgran, V., Caufield-Noll, C. et al. Comparison of universal screening in major lynch-associated tumors: a systematic review of literature. Familial Cancer 21, 57–67 (2022). https://doi.org/10.1007/s10689-020-00226-w

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  • DOI: https://doi.org/10.1007/s10689-020-00226-w

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