The LKB1/Lung Cancer Connection

A Report by Stephanie Sugars

First off, a disclaimer. There really isn't much incidence in the literature of lung cancer in PJS folks, certainly no where near the numbers of gastrointestinal (GI), pancreatic, breast or reproductive cancers and tumors. Dr. Giardiello wrote about the very high risk of cancer in familial cancer¹ and the absolute risk for lung cancer was 15%, well below the estimated cancer risk for many other organs. I am aware that lung cancer in PJS folks might be under reported in the literature because most authors have focused on GI malignancy to the exclusion of all other types of cancers and tumors. Even reproductive tumors haven't been considered part of the syndrome until recently and some physicians, especially gastroenterologists, still discount the gynecological and testicular problems of PJS folks. All the information isn't in yet.

A report from Johns Hopkins suggests a link between inactivation of LKB1 and sporadic lung adenocarcinomas.² Inactivation of LKB1 occurs when both working copies of the gene are knocked out. This is roughly analogous to loss of heterozygosity (LOH). As I've written before, most people with PJS have one working and one non-working copy of the LKB1 gene, whereas other people have two working copies of the gene. It was thought that when the one working copy lost function through a mutating event that polyps, tumors and cancers arose. Loss of the working copy is called loss of heterozygosity.

Anyway, this report is NOT about people with PJS getting lung cancer, but about lung cancers in the general population or sporadic cancer. The researchers found inactivation of LKB1 in many lung adenocarcinomas. I have to backtrack here with a bit of history. After the genetic locus for PJS was pinpointed in 1997, researchers began testing for inactivation of LKB1 in a variety of cancers associated with PJS including breast, cervical, colon, testicular, gastric and ovarian. (I won't give you footnotes on these, but am happy to dig them up.) Most studies didn't find a connection between inactivated LKB1 and the cancers, which discouraged researchers from looking for connections between LKB1 and cancers less common in PJS.

Research into rare genetic conditions like PJS (LKB1 OR STK11 gene), Familial Adenomatous Polyposis (APC gene), Li-Fraumini syndrome (p53 gene), Cowden syndrome (PTEN gene), BRCA1 and BRCA2 give scientists insight into the mechanisms of cancer. There are basically two main types of hereditary predisposition to cancer -- oncogenes and tumor suppressor genes. Think of them like accelerator and brakes. Oncogenes make cancer go, tumor suppressors make them stop. LKB1 is a tumor suppressor gene, so when both copies are knocked out, then cancer or other tumors are no longer suppressed and can grow. There are many pathways to cancer and many genes involved, some genes involved in carcinogenesis are related to inherited predisposition to cancer syndromes, others aren't.

Dr. Sanchez-Cespedes’ group was surprised to find a connection between LAD tumors and mutations that inactivate LKB1 because other researchers had not found a strong link between such mutations and other sporadic (non-inherited) tumors, including breast and colorectal cancer. One-third of the 41 lung adenocarcinomas analyzed showed inactivation of LKB1. This news supports more research into LKB1. Since over 50,000 people in the USA develop lung adenocarcinoma annually, there may be interest and funding for more studies of LKB1 that will ultimately affect us.

As I wrote, I've been collecting lung cancer cases. There are two topics in my mind, one is a group member who's had a lung hamartoma and the second is the connection between cigarette smoke and lung, colon, breast and other cancers.

Following is a table with reports of lung cancer from the literature and outside of the literature.

In March 2003, Dr. Sanchez-Cespedes' group published a new paper on the LKB1-lung cancer pathway.¹² I have only read the abstract, not the article, but the findings are interesting for a couple of reasons. When the researchers introduced overexpressed LKB1 into lung adenocarcinomas cells it led to cell-growth suppression. I assume this is in a laboratory, not a person. They then analyzed the changes in gene expression and found that "growth suppression in A549 cells overexpressing LKB1 may be mediated by p53. In addition, PTEN up-regulation indicates that LKB1 could be involved...". Other researchers have found connections between PJS and p53 and PJS and PTEN.^{13, 14} Remember: p53 mutations cause Li-Fraumeni syndrome and PTEN mutations lead to Cowden syndrome. Interestingly, another study found that LKB1 didn't follow another common cancer pathway (ras).¹⁵

I am not suggesting any screening or prevention for lung cancer, nor have I read that any is suggested by any PJS expert. This patient view isn't meant to depress or scare anyone. As I wrote earlier, lung cancer seems to be the least of our worries. I'm actually encouraged because I hope that research interest and money will continue to flow into PJS so that we get better prevention, screening and treatment.

© 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: 20.May'04