New Research Says Universal Lynch Syndrome Testing Should Be Expanded

While universal screening for Lynch syndrome is currently only recommended for patients with colorectal and endometrial cancers, a new study recently published in The American Journal of Surgical Pathology suggests this for patients with upper tract urothelial carcinoma, too.

DNA mismatch repair occurs when mistakes happen during DNA replication. Due to defects in the way that DNA in cancer cells repairs itself, it creates changes and mutations to normal cells that can eventually turn into cancer. Mutations in DNA mismatch repair genes result in a failure to repair errors in repetitive sequences, leading to microsatellite instability.

Deficiencies of the genes most frequently responsible for causing microsatellite instability-high cancers — such as colorectal and endometrial cancers – are most often associated with a syndrome called hereditary non-polyposis colorectal cancer syndrome, which is commonly referred to as Lynch syndrome.

Defined by germline mutations in DNA mismatch repair genes, Lynch syndrome is a genetic disease that dramatically increases the risk of multiple malignancies, including colon and endometrial, of which more than 60 percent of patients with the genetic condition will develop these cancers.

Universal screening of all patients with these malignancies has become standard of care, as identifying Lynch syndrome not only helps the patient remain vigilant of other cancers, but also gives family members the information they need to monitor their own health.

After gastrointestinal and gynecologic tumors, upper tract urothelial carcinoma is the third most common cancer, occurring in 4 to 6 percent of patients with Lynch syndrome. However, the uniform guidelines for Lynch syndrome screening that exist for other malignancies do not exist for upper tract urothelial carcinoma.

Screening is usually performed in patients with colorectal and endometrial carcinomas via immunohistochemistry that looks for the loss of MLH1, PMS2, MSH2, and/or MSH6 protein expression. In these cancers, the authors explained, “dual deficiency of MLH1/PMS2 is the most common mismatch repair loss pattern.”

However, according to the study, different deficiencies exist in patients with upper tract urothelial carcinoma. “Unlike colorectal and endometrial carcinomas, (mismatch repair) deficiency in (upper tract urothelial carcinoma) most commonly manifests as dual loss of MSH2 and MSH6 or pure MSH6 loss, with consistently retained MLH1 and PMS2 expression.”

Because these deficiencies express themselves differently in upper tract urothelial carcinoma, researchers evaluated whether universal screening is appropriate for this patient population by comparing mismatch repair expression and microsatellite status with patients diagnosed with bladder urothelial carcinoma.

“Although clinical criteria such as family or personal history of cancer can be helpful in narrowing down patients who might be at risk for colon or uterine cancer in Lynch syndrome, our study and others have found this less helpful in upper tract urothelial cancer,” study co-author Helen Cathro, MBChB, head of the University of Virginia’s Division of Renal Pathology, said in an interview with CURE. “This is why we are suggesting that relatively inexpensive immunohistochemical testing be performed on these tumors, which can be followed up with molecular testing if positive.”

To come to this conclusion, Cathro and her colleagues reviewed tissue samples of 117 patients with upper tract urothelial carcinoma (77 men and 40 women) and 160 patients with bladder urothelial carcinoma (110 men and 50 women) and found that 9 percent of patients with upper tract urothelial carcinoma showed mismatch repair protein loss by immunohistochemistry, while only 1 percent of patients with bladder urothelial carcinoma demonstrated such deficiencies. Additionally, 40 percent of patients with upper tract urothelial carcinoma were deemed microsatellite instability-high, compared to zero percent of patients with bladder urothelial carcinoma.

When the researchers combined their results with other studies, they determined that Lynch syndrome is present in 1 to 3 percent of all upper tract urothelial carcinoma cases and in 2 to 6 percent of both colorectal and endometrial cancers.

Because Lynch syndrome is related to a similar percentage of upper tract urothelial carcinoma cases, and this malignancy is relatively rare, the researchers suggested that mismatch repair protein loss by immunohistochemistry screening should be followed by microsatellite instability testing and included in diagnostic guidelines for all patients with upper tract urothelial carcinoma going forward.

“Patients with this tumor who have Lynch syndrome are also at greater risk for colon and endometrial cancer than the general population and need more frequent screening beginning at an earlier age,” said Cathro. “Their family members are also at risk for Lynch syndrome and the associated carcinomas and should also undergo genetic testing and most importantly genetic counselling.”

In addition to providing genetic insight, identifying the microsatellite stability status of these patients could also have positive treatment implications, as Keytruda (pembrolizumab) has been approved for the treatment of microsatellite instability-high or mismatch repair deficient solid tumors, including those found in upper tract urothelial carcinoma.