ASCO 2018: MSI-High Status Linked To Lynch Syndrome Across Range Of Tumour Types

Microsatellite instability-high tumour patients and their families may benefit from screening for Lynch syndrome

medwireNews: Patients with microsatellite instability (MSI)-high tumours have an increased likelihood of Lynch syndrome, say researchers who discovered that the risk was not limited to patients with colon or endometrial cancer.

The research was reported at the ASCO Annual Meeting 2018, held in Chicago, Illinois, USA, by Alicia Lathan Schwark, from Memorial Sloan Kettering Cancer Center in New York, USA.

In all, 15,045 tumour specimens, taken from patients with over 50 types of cancer, were examined for MSI using the MSK-IMPACT next-generation sequencing platform, while germline analysis was performed for the mismatch repair (MMR) genes associated with Lynch syndrome, namely MLH1, MSH2, MSH6, PMS2 and EPCAM.

MSI-high status – defined as a score of 10 or above – was most common in patients with colon cancer (25%) and endometrial cancer (16%), followed by those with colorectal (14%) and gastric cancer (6%).

And germline MMR gene mutations were most common in the 326 MSI-high patients, at 16.3% versus 1.9% of the 699 patients with MSI-indeterminate status (score 3–<10) and 0.3% of the 14,020 patients with MSI-stable status (score <3), the last of which the presenter described as being “in line with general population prevalence estimates.”

Of the patients diagnosed with Lynch syndrome, 43% of the patients MSI-high tumours and 77% of the patients with MSI-indeterminate tumours – encompassing 50% of these 66 Lynch cancer patients overall – did not have colorectal cancer or endometrial cancer. Instead, the patients had tumours not previously associated with Lynch syndrome, most commonly urothelial (37.5%).

Further analysis revealed that 88% of Lynch syndrome patients with MSI-high or indeterminate status had a tumour signature indicating MMR-D tumour mutational signature whereas 89% of Lynch syndrome patients with MSI-stable disease did not have this mutation signature, a significant difference.

“Taken together, this suggests that germline MMR mutations among the high and indeterminate groups were likely causative of the patients’ cancer, while those among the [MSI-stable] group were likely incidental”, summarised Alicia Lathan Schwark.

“In other words, Lynch syndrome patients who had MSI high or indeterminate tumours their tumours were likely caused by their Lynch syndrome, while those who were found to have [MSI-stable] tumours, these tumours were likely not caused by their Lynch syndrome.”

Although all the Lynch syndrome patients with MSI-high or indeterminate colorectal and endometrial tumours met clinical criteria for Lynch syndrome testing, only 54.5% of the 33 patients with other tumour types did so based on personal or familial criteria.

“The data supports that if a MSI-high or MMR-D tumour is identified, regardless of that patient’s cancer type or their family cancer history, genetic testing for Lynch syndrome should be done”, Alicia Lathan Schwark concluded.



Schwark AL, Srinivasan P, Kemel Y, et al. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome . J Clin Oncol 36, 2018 (suppl; abstr LBA1509).

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