Microsatellite analysis of sporadic and hereditary gynaecological cancer in routine diagnostics

Abstract

Microsatellite instability (MSI) testing is tricky in gynaecological cancers (GC). Thus, we aimed to describe the instability patterns to improve MSI test interpretation in sporadic and hereditary GCs. Ninety-five cases, including uterine and ovarian cancers, with known genetic and immunohistochemical (IHC) features, were analysed for MSI by a mononucleotide repeats pentaplex (MRP). We identified 13 ambiguous cases that did not fully meet MSI criteria ('borderline' cases, B-MSI), which were mainly represented by MSH2/MSH6-deficient and Lynch syndrome cases. Also, we evaluated nine additional loci of candidate MSI markers that did not improve the detection of MSI cases, but might be useful for discordant or borderline samples. In conclusion, although MSI and IHC test are highly concordant, a subset of ambiguous MSI cases deserves a careful interpretation in particular when MSH2/MSH6 are involved. and testing may be useful to integrate MRP panel for the analysis of critical cases.

Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

“…Wong et al observed that the NCI recommended panel of markers were not useful for analysis of MSI status in cervical cancer and suggested that using more than five markers can improves the MSI detection [64]. Similarly, it was reported that a MSI pentaplex marker panel was not sensitive and specific in screening gynecological dMMR/MSI cancers [86]. With the advent of next-generation sequencing (NGS), several computational tools for MSI detection were established, however, there is an urgent need to develop MSI panels which are specific and sensitive for each gynecological cancer types.…”

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…Tumor type. The sensitivity of MSI has been shown to be lower in non-CRC tumors, especially in endometrium, brain, and urothelial tumors, as a consequence of fewer unstable markers and a shorter instability length [25,69,117,118,[121][122][123][124][125]. For example, MSI is particularly difficult to detect in brain tumors, with less than 20% of brain tumors from patients with LS (or CMMRD) exhibiting MSI [69,105,[126][127][128].…”

“…MSI-L colorectal tumors were not shown to differ in their clinicopathologic features or in most molecular features from MSS tumors, leading to consider MSI-L and MSS tumors together and to regard as MSI only MSI-H tumors [129]. However, the sensitivity for LS detection generally increases when MSI-L is considered to be a positive test result (>90% vs. 67-100%) but with lower specificity (45-85% vs. 61-93%) [12,123,[130][131][132][133]. As MSI testing is a screening test and not a final diagnostic test, some authors suggest to take into account the MSI-L results to perform constitutional genetic testing [131].…”

Serous ovarian carcinoma in patients with Lynch syndrome: Caution is warranted

“…The authors performed neither MMR IHC nor MSI testing to confirm that cancers were indeed due to Lynch syndrome. The vast majority, if not all Lynch syndrome-associated ovarian carcinomas, show MMR protein expression loss and/or microsatellite instability ( Akbari et al, 2017 ; Libera et al, 2017 ). Furthermore germline mutations in the BRCA1/2 and RAD51C/D ovarian cancer susceptibility genes were not formally excluded.…”