Cancer and Your Genes

Mutations in the DIS3L2 Gene Cause Perlman Syndrome: Another Key Clue in Unraveling the Puzzle of Wilms Tumor Development

Wilms tumor (also referred to as nephroblastoma) is a relatively uncommon pediatric cancer (about 1 out of every 9,000 children are affected) - although it is the most common of the childhood cancers involving the kidney.

Sometimes, Wilms tumor occurs "sporadically" - showing up in the kidney on one side and not associated with other tumors or congenital anomalies.  However, Wilms tumor can occur much more frequently in the context of several different syndromes.

For example, it can occur more commonly in individuals with the so-called WAGR syndrome, in which the "W" refers to Wilms tumor, the "A" refers to aniridia (absence of the iris of the eye), the "G" refers to genital anomalies, and the "R" refers to developmental delay (previously referred to as mental retardation).  WAGR syndrome is associated with deletions of a region of chromosome 11 (11p13 to be exact), and we now know that while aniridia in WAGR occurs because of deletion of a gene called PAX6, the risk for Wilms tumor in individuals with 11p13 deletion is due to the deletion encompassing a gene called WT1.  Other individuals born with mutations in WT1 can have other syndromes (including Frasier syndrome and Denys-Drash syndrome) or sometimes develop Wilms tumor without any other features of a syndrome. 

Other genes and syndromes are also known to be associated with Wilms tumor development.  A complete description of all of them is beyond the scope of this post, but I'll just briefly mention one other genetic cause: biallelic BRCA2 gene mutations (i.e., a deleterious mutation in both copies).  Thus, in the relatively small number of people who are known to be unlucky enough to have biallelic BRCA2 mutations, Wilms tumor is relatively frequent.

Perlman Syndrome and Wilms Tumor

Another syndrome in which Wilms tumor occurs is Perlman syndrome.  In fact, for infants with this syndrome who survive past the neonatal period, nearly two-thirds will develop Wilms tumor.  Infants with Perlman syndrome have features of overgrowth disorders.  As in a number of cancer predisposition syndromes, individuals with Perlman syndrome are more likely to develop bilateral (two separate primary tumors on both sides of the body) tumors and also tend to develop Wilms tumor at a younger age than is typical.

A New Study Has Identified a Gene for Perlman Syndrome

Perlman syndrome is extremely rare; however, clinicians and scientists have actively sought a genetic cause for this disease both to facilitate counseling and care for Perlman syndrome families and to learn more about how Wilms tumor develops.  In a new study reported online in the journal Nature Genetics, Dewi Astuti, Mark Morris, Eamonn Maher and their colleagues studied six families in which one or more children were affected with Perlman syndrome. 

After mapping the responsible gene (with a technique called "autozygosity mapping") to chromosome 2q37.1, they were able to identify mutations in a gene called DIS3L2 as the cause of this autosomal recessive condition.

They went on to do quite a bit of work digging into the potential function of this gene - which I won't go into here - and also beginning to assess the role that mutations in this gene might play in Wilms tumors that are not associated with Perlman syndrome.

They found mutations or deletions of DIS3L2 (that probably occurred "somatically" during tumor development rather than being something that the child was born with) in a substantial fraction of the 40 other Wilms tumors that they studied.

Key Implications of This Study

A number of key implications arise from this study.  Here are a few:

1. Identification of a causative gene for Perlman syndrome will help clinical geneticists and genetic counselors provide key information and management recommendations to families with one or more children with Perlman syndrome.
2. The demonstration that the DIS3L2 gene is important in protecting against Wilms tumor development will lead to future studies that potentially look at its role in Wilms tumor prognosis and in the distant future theoretically could lead to new treatments.
3. There are a few hints that DIS3L2 might be involved in the development of some other, more common, cancers.  This study may just be the tip of the iceberg.

Selected References

Astuti D, Morris MR, Cooper WN, et al.  Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.  Nature Genetics 2012 (published online before print Feb 5 2012)

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About the Author: Matt Mealiffe, M.D. is a Clinical Cancer Geneticist with dual board certification in Clinical Genetics and Internal Medicine.  He received his undergraduate degree at Stanford University, his M.D. at the Yale University School of Medicine, and did his residency and fellowship training at the University of Washington.  Dr. Mealiffe writes at CancerAndYourGenes.com to cut through the hype surrounding personalized medicine and improve the public's understanding of what we really know - and don't know - about the connection between our genes and cancer risk.

Childhood Cancer and Birth Defects

It is now well known that certain clinical genetic syndromes recognized in childhood are associated with an increased risk of cancer development.  For example, in the Gorlin syndrome (also known as Nevoid Basal Cell Carcinoma Syndrome), which may affect ~1 in 40,000 individuals, a mutation in the PTCH gene leads to a number of unusual features including multiple jaw cysts, a very large head circumference, and prominent foreheads in addition to skeletal (bifid ribs and wedge-shaped vertebrae) and other anomalies.  Although the causative mutation in PTCH leads to these morphological abnormalities, it also leads to a substantial increase in cancer risk, primarily for skin basal cell carcinomas and medulloblastoma.

Although a number of studies have tried more broadly to assess the association between various birth defects (major malformations and minor anomalies) and cancer, these have been plagued by limitations including the reliance on chart reports of the morphological abnormalities.

A new study, reported in the January 2 issue of JAMA, provides an intriguing new look at this issue. 

The authors personally examined a total of 1073 childhood cancer patients and 1007 controls individuals (all patients and controls were of northern European descent) without cancer with an eye toward cataloging "morphological abnormalities" (both major birth defects and minor anomalies) in a standardized fashion.

Interestingly, they found that both major birth defects and minor anomalies were significantly more common in the pediatric cancer group as compared to controls.  For example, per 1000 individuals, 268 major abnormalities were found in cancer patients vs. 155 in controls; likewise, there were 1252 minor anomalies per 1000 individuals in cancer patients vs. 898 per 1000 controls.  This was statistically significant and is consistent with the notion that at least a subset of pediatric cancers are associated with genetic defects that might also predispose to combinations of birth defects and/or minor congenital anomalies. 

In 42 patients, there was an already established clinical genetic syndrome.  Even after these patients were removed from the analysis, there was still a significantly higher number of major abnormalities and minor anomalies in the cancer patients as compared to controls.

After excluding the 42 patients with preexisting diagnoses, the authors sought to assess which congenital anomalies seem to be particularly associated with pediatric cancer.  For example, they showed that blepharophimosis (a static reduction in the distance between the upper/lower eyelid resulting in a narrowed slit-like appearance), a minor anomaly, was about 11-times more likely to be found in pediatric cancer patients as compared to controls.  Some of the other abnormalities that were statistically associated with pediatric cancer were asymmetric lower limbs and broad feet (appearing disproportionately wide for length and for which the measured width is >95th percentile for age).

The authors then went on to make some initial attempts to identify patterns of morphological abnormalities to classify them into putative new syndromes.

Overall, this study is very intriguing, but has some methodological limitations that will require validation of the result in an independent group of patients and controls.  Nevertheless, this is a very plausible result supported by the existence of a number of known genetic syndromes in which certain birth defects cluster with certain types of cancer. 

This study provides a foundation on which future efforts to identify new tumor predisposition syndromes will be based.  Ultimately, this should allow improved efforts to screen for and/or prevent some childhood cancers.