This Paper of the Month report considers the role of microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) screening in patients with Lynch syndrome-associated cancer predisposition across colorectal cancer and other solid tumours.

Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. Latham A et al. Senior Author: Stadler ZK. J Clin Oncol 2018 Oct 30: JCO1800283. Doi:10.1200/JCO.18.00283 (Epub ahead of print).

What is known on the subject

In 1993, the first described genetic phenomenon of microsatellite instability (MSI) was correlated to inherited colorectal cancers in the setting of Lynch syndrome. Subsequently the phenomenon was attributed to deleterious germline variants such as MSH2 and MLH1 and other supposedly less frequent DNA mismatch repair (MMR) genes. MSI testing was immediately recognized as a reliable pretest to select CRC patients who should undergo further testing, and predictive germline testing of individuals and families was implemented into clinical practice. The clinical Amsterdam and Bethesda criteria were soon found to be inadequate and systematic MSI testing (or immunohistochemistry for MMR proteins) in unselected colorectal and endometrial tumors was implemented as routine practice in dedicated centers, resource permitting.

Most recently, however, MSI has been demonstrated to be a strong predictor of response to immune checkpoint inhibitor therapy in the setting of advanced cancers. This led to FDA approval of pembrolizumab for any treatment-refractory MSI cancer regardless of the primary site – a paradigm changer that has unfortunately not (yet) been pursued in Europe. This has led to a scientific lobby recommending the evaluation of MSI status for virtually any advanced solid tumor as a cheap, straightforward evaluation of any advanced cancer in order to identify patients that may benefit from immunotherapy.

What this study adds

The manuscript by Latham et al. [1] demonstrates the potential of MSI testing as a biomarker for identification of Lynch syndrome regardless of primary tumor site and clinical features. This study provides extensive data on well-annotated tumor and matched normal DNA sequencing results with paired germline MMR gene testing from more than 15,000 patients, and encompassing more than 50 different types of primary cancer. Not surprisingly, colorectal and endometrial cancers accounted for the majority with high-level MSI (MSI-H), but 38% (125 of 326 tumors) with MSI-H and more than 90% of those with intermediate-level MSI (MSI-I) were other cancer types.

Germline testing confirmed a diagnosis of Lynch syndrome in 16.3% and 1.9% of tumors with MSI-H and MSI-I status, respectively (and in 0.3% tumors that lacked MSI). Importantly, half of all Lynch syndrome probands whose tumours harbored MSI-H/I had primary cancers other than colorectal or endometrial cancers, including various malignancies not known to be linked to Lynch syndrome (e.g. melanoma, sarcoma, mesothelioma); nearly half of such probands failed to meet clinical criteria for Lynch syndrome germline evaluation on the basis of their personal/family histories of cancer indicating that these would almost certainly have gone undetected by routine clinical care.

Implications for colorectal practice

The paper underlines the paramount value of MSI testing across all tumor types as a screening tool for Lynch syndrome. Lynch syndrome is now recognized as markedly more common than originally assumed when MSI was first discovered. One recent study estimated that the general population prevalence of Lynch syndrome is roughly 1 in 280, which puts it on par with BRCA1/2-associated hereditary breast/ovarian cancer. Nonetheless, the identification and awareness of Lynch syndrome lags far behind that of hereditary breast/ovarian cancer despite various national guidelines that recommend universal tumor and endometrial cancers as a screen for Lynch syndrome [2].

Lynch syndrome as yet is still largely underdiagnosed. Furthermore, the phenotypic expression of Lynch syndrome varies by type of altered MMR gene, and its broad constellation of associated malignancies makes it challenging to identify Lynch syndrome by clinical criteria alone; this difficulty has been supported by the results of the findings by Latham and others.

Lynch syndrome remains largely underdiagnosed due to the inaccuracy of clinical criteria and the findings in this paper underline the phenotypic variability of the syndrome. Universal tumor testing (NGS panel testing) will rapidly be implemented due to its value for targeted therapy, and decreasing costs could lead to large-scale application and identification of genetically-frequent hereditary predisposition. Clinicians must be prepared to understand the risk assessment and significance of the penetrant and less-penetrant MMR genes. Surgeons must aware of the available risk-reducing strategies, including screening, chemoprevention with ASS among others and prophylactic surgery. The most meaningful (unbiased) risks are likely to come from prospective analysis and several game-changing papers have been published based on the PLSD (Prospective Lynch Syndrome Database) [3]. Clinicians may reference the online risk assessment tool based on the prospective Lynch syndrome registry ( 

  1. Microsatellite Instability is Associated With the Presence of Lynch Syndrome Pan-Cancer. Latham A; Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Niddha Sm Hechtman J, Zehr A, Dubard-Gault M, Tran C, Stewart C, Sheehan M, Penson A, DeLair D, Yaeger R, Vijai J, Mukherjee S, Galle J, Dickson MA, Janjigian Y, O’Reilly EM, Segal N, Saltz LB, Reidy-Lagunes D, Varghese AM, Bajorin D, Carlo MI, Cadoo K, Walsh MF, Weiser M, Aguilar JG, Klimstra DS, Diaz LA Jr, Baselga J, Zhang L, Ladanyi M, Hyman DM, Solit DB, Robson ME, Taylor BS, Offit K, Berger MF, Stadler ZK. J Clin Oncol 2018 Oct 30: JCO1800283. Doi:10.1200/JCO.18.00283 (Epub head of print)
  2. Tumor Testing for Microsatellite Instability to Identify Lynch Syndrome: New Insights Into an Old Diagnostic Strategy. Yurgelun M, Kastrinos Fay. J Clin Oncol 2018 Doiorg/10.1200/JCO.18.01664.
  3. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. Gut. 2018 Jul;67(7):1306–16. 
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