To the Editor: We read the review by Goodenberger et al.1 on colorectal surveillance guidelines for PMS2 mutation carriers with great interest. However, we would like to address two issues by adding data from our cohort consisting of 415 confirmed PMS2 mutation carriers (the majority of which were recently published (n = 367) but not included in the article by Goodenberger et al.1) to offer further perspective on PMS2 specific guidelines.2

First, we would like to emphasize the difference between index carriers and mutation-positive family members when assessing the appropriateness of surveillance guidelines. As the authors rightly point out, colorectal cancer (CRC) at less than 30 years of age could be due to digenic inheritance or a modifier gene because young CRC patients appear to have a relatively low incidence in PMS2 families. Indeed, the authors note that none of the index carriers with CRC at more than 30 years of age reported a positive family history for CRC diagnosed at younger than 30 years. All colorectal cancers diagnosed at an age younger than 30 (n = 7) except one belonged to an index carrier. In the family in which a nonindex individual developed CRC before age 30, the patient died soon after diagnosis and before a PMS2 mutation in the index was identified. There is thus no evidence in either of the two cohorts, with a combined number of ~300 families, that family members have a high or even moderate risk of developing CRC before age 30, even in this group of highly selected families. Therefore, surveillance starting at age 25—as advised by Goodenberger and colleagues—is not appropriate in our opinion. However, we do agree with the authors that first-degree family members of a young patient with CRC should be counseled accordingly about the possibility of another mutation in a modifier gene and given appropriate surveillance advice, i.e., start surveillance 2–5 years earlier than the age at which the index carrier was diagnosed.

Second, the authors note that the group of mutation carriers with CRC diagnosed before age 30 appears to be a distinct group, indicating the possibility of an additional—second—germ-line mutation. One notable finding herein is that in their cohort all cases had left-side CRC, a nontypical location for Lynch syndrome–associated CRC. Even though this finding was statistically significant, we advise caution in the interpretation of these findings because in our cohort 57% (4/7) of the young CRC patients presented with right-side CRC. This difference illustrates the need for very large cohorts, which can be achieved only through global collaboration.

In conclusion, we believe that, although patient preference should always be taken into account, the combined data from Goodenberger and colleagues’ study and ours provide enough evidence to support starting CRC surveillance in monoallelic PMS2 mutation carriers at age 30. First-degree relatives of index carriers (siblings and children) who presented with CRC before age 30 should be exempt from this rule and start 2–5 years earlier than the age at which this index was diagnosed with CRC.

Disclosure

The authors declare no conflict of interest.