Yi-Qian Nancy You, MD, MHSc
To properly manage patients with DNA mismatch repair deficiency (dMMR) rectal cancer, one must have a well-rounded understanding of the molecular and clinical causes and risks associated with this subgroup of patients. Ongoing and future endeavors in this setting are paving the way for precision medicine, said Yi-Qian Nancy You, MD, MHSc, one of the study authors on a report published in the Journal of Clinical Oncology
, which addressed gene alterations and treatment for patients with dMMR rectal cancer.1
For patients with colorectal cancer, identification of dMMR triggers the need for genetic testing for the detection of a potential heritable germline deficiency in the DNA mismatch repair system. The implications of dMMR status are still unknown in rectal cancer, however, meaning that genetic testing has rarely occurred.
When genetic testing is performed on dMMR rectal cancer patients, a separation occurs between patients who present with mutations in their tumors in the mismatch repair system as well as the same mutations in the germline, and those who do not show the same mutations in the germline as can be found in their tumors.
Historically, this group has been clinically considered to have Lynch syndrome because there’s been no evidence to the contrary. Therefore, this subgroup of patients, along with their family members, would be considered to have a high lifetime risk of developing cancer and would subsequently require extensive screening.
“At some point when we figure out what’s going on with these people—what led to their tumor mutation if it’s not in the germline...then maybe we won’t need to keep them in this high-risk screening program and test them for all of these other Lynch-associated tumors,” said You, associate professor of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, in an interview with OncLive
However, this group, often termed “Lynch-like syndrome” by many reports, stands apart from those with Lynch syndrome. These patients have nonsporadic high microsatellite instability tumors, abnormal immunohistochemistry of the MMR proteins in the tumor, and no evidence of MLH1 hypermethylation or BRAF mutation. Also, genetic testing in these patients show various unclassied variants that are likely nonpathogenic, or results are inconclusive, whereas patients with true Lynch syndrome have identifiable pathogenic mutations.2
It is possible that these patients may not require as extensive screening as those with Lynch syndrome would.
One population-based study examined the risk of cancer in families of patients with “Lynch-like syndrome” in comparison with families of Lynch syndrome patients.3
The study found that the familial risk is reduced with Lynch-like syndrome compared with Lynch syndrome. The standardized incidence ratio (SIR) for colorectal cancer (CRC) for Lynch-like syndrome was 2.12 (95% CI, 1.16-3.56) compared with 6.04 for classic Lynch syndrome (95% CI, 3.58-9.54; P <.001). However, the SIR for Lynch-like syndrome was higher than the SIR for sporadic CRC of 0.48 (95% CI, 0.27-0.79; P <.001), confirming the need for surveillance of these families, although not to the extent of Lynch syndrome families.
The community does not yet have a consensus on not only how to manage these patients, but also regarding what to call this subgroup, commented You. She has proposed that these patients be termed “mutation-negative Lynch syndrome.” This phrase would differentiate these patients from the classic Lynch syndrome and nod to the fact that genetic testing shows unknown MMR genes in these patients.
The basis for “mutation-negative Lynch syndrome” needs to be understood in order to differentiate cancer treatment and surveillance for these patients and their family members. You and colleagues’ study of dMMR in rectal cancer aimed to begin to identify the molecular basis of this patient population compared with Lynch syndrome patients, and to begin to identify which treatment would most benefit these patients.
In the study a selection of 62 patients over the age of 18 years old with dMMR rectal adenocarcinoma, who were diagnosed between 1992 and 2012, were tested for tumor MMR status, microsatellite instability, and immunohistochemistry of the MLH1, MSH2, MSH6, and PMS2 proteins.1
Patients with detected deficiency in MLH1, MSH2, MSH6, or PMS2 underwent genetic counseling for confirmatory germline mutation testing. Forty-two patients had true Lynch syndrome and 15 patients had mutation-negative Lynch syndrome, 7 of which had presented with a variant of unknown significance (VUS), all of which were missense mutations, and 8 had uninformative negative results. The remaining 5 patients had declined genetic testing.