Unsolved Mysteries

A Report by Stephanie Sugars

A letter from a group member about PJS genetic testing got me thinking about PJS unsolved mysteries. One of them is whether all PJS folks have the STK11/LKB1 mutation on chromosome 19p13.3. When that mutation site was found in 1998, nearly all the PJS patients had a mutation there. Not the same mutation, in fact by 2003 nearly 80 distinct mutations were described. (Boudeau, 2003). But, five years ago most researchers agreed on the genetic cause of PJS. Since then it is clear that there is more than one mutation site (genetic heterogeneity) for PJS. The end of this report lists many research findings on the frequency of this mutation in PJS patients.

After analyzing PJS patients for the mutation, many researchers began analyzing the cancers of people who don't have PJS to find out whether it is mutated in "sporadic" cancers. This is a fairly common practice -- to identify a hereditary cancer syndrome, find the genetic locus for that syndrome, find that locus in affected patients, then explore whether that locus is mutated in cancers of people who don't have the syndrome. The most "famous" of these cancer-predisposing syndromes is Li-Fraumeni syndrome which affects something like 300 people worldwide and confers a tremendously high risk of multiple cancers. People with Li-Fraumeni have a p53 mutation at birth and undergo "second hits" during life which lead to cancer. Researchers found that p53 is mutated in many cancers of people who don't have Li-Fraumeni; and that PJS is associated with p53.¹

When researchers found few STK11/LKB1 mutations in cancers of people who don't have PJS, they stopped that line of investigation and went on to develop mouse and fly models with STK11/LKB mutations. I've written about these developments in PJS genetics advances for this group during the past three years. But I've not reported much on "genetic heterogeneity" in PJS. Genetic heterogenity (hetero=different, geneity=gene) means that different mutation sites can lead to a genetic condition.

Although early reports indicated that most PJS folks had a mutation of STK11/LKB1 at chromosome 19p13.3, later reports didn't confirm that finding. What follows are different reports of the frequency of this mutation in PJS patients. I've included quotes from a couple of the articles to provide more detail.

If a PJS person doesn't have a mutation at the known site, other family members cannot get genetic testing. If a patient's genetic screening is negative or inconclusive for the mutation, then their children must be treated as if they have PJS and undergo screening for polyps including scopes and x-rays - expensive, traumatic procedures with risk of complications. If a patient's mutation can be found, then offspring can be tested for that mutation and those with the mutation will undergo screening for polyps, while those without the mutation won't need to do it. Finding another PJS site or locus would benefit families whose mutation isn't at the known site. Researchers have begun to search for a second PJS locus.²And a possibility on chromosome 2q36 was suggested in an earlier article by Smith et al.³

Hopefully researchers will continue to explore possible alternate mutation sites for PJS. Finding other sites will, at minimum, help those families who don't have a mutation at the known site. It may also lead to understanding and treatment of people with PJS. And finally, it may contribute to prevention, treatment and cure of cancer in the general population.

There is much more to be written about this interesting topic. Hopefully some of you will look at the references in this article. The numbers of PJS folks with and without the mutation and also the authors, titles and dates of the articles give an emerging picture of genetics research into PJS.

Note: Statistically, it is likely that the above samples were taken from a normal PJS population. The results are not unexpected, from a statistics view. Of course, this is coming from a very amateur statistician. If you find my conclusion is faulty, please do not hesitate to let me know by using the Email Webmaster link at the bottom of the page. --Ed.

© 2004 by Stephanie Sugars, all rights reserved, used by permission. No part of this article may be reproduced in any form without written permission from the author.

Contact Stephanie Sugars at PJ4Steph@aol.com

Update: 19.May'04