By David N. Leff

People who live in the rarified, high-altitude atmosphere of the 5,000-mile-long ¿ up to 22,000 feet high ¿ Andes mountain range in South America are prey to paraganglioma ¿ a benign tumor of oxygen deprivation.

Paradoxically, the largest known population of this disorder in the industrialized world ¿ some 50 recorded cases ¿ occurs in The Netherlands, a country with the lowest altitude in Europe. In the U.S., one center of paraganglioma [PGL] research ¿ at the University of Pittsburgh ¿ has catalogued over 30 families with the disease.

There, molecular geneticist Bora Baysal is a pioneer researcher of PGL¿s rare inherited form. He is senior author of a paper in today¿s Science, dated Feb. 4, 2000, which bears the title: ¿Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.¿

¿PGL is diagnosed in patients,¿ Baysal told BioWorld Today, ¿by the fact that its noncancerous tumors all arise in a walnut-sized cluster of highly vascularized cells in the neck, called the carotid body (CB). This dense cluster of blood vessels is intimately associated with the carotid artery, which bifurcates in the neck into internal and external branches. The CB is located at the junction, the bifurcation point. It is extremely vascular because non-stop oxygen sensing in the blood is its only known function.¿

Baysal rates the prevalence of PGL in industrialized countries at one case in 30,000. ¿The hereditary portion of this figure,¿ he observed, ¿is variously estimated to be 10 [percent] to 50 percent. The rest are called sporadic. We estimate that 50 percent of all affected carotid bodies (CB) are probably genetic; the other 50 percent somatic.¿

Like an orbiting satellite, scanning the earth¿s atmosphere for life-threatening levels of ozone (O₃), the body¿s CB monitors levels of life-giving oxygen (O₂) in the bloodstream. The arterial network conveys this molecular oxygen to every organ, tissue and cell in the mammalian body. If its supply to the heart flags, ischemia and heart failure ensue; in the brain, stroke occurs; in the limbs, gangrene.

Growing Tumor Cells Wolf Down Oxygen

Chronic atmospheric hypoxia ¿ reduced oxygen level ¿ was originally linked to paraganglioma tumors in the carotid bodies of people living at high altitudes. This shortage constantly stimulated the CBs, leading their cells to proliferate, benign tumors to develop, and their oxygen-sensing ability to drop.

Baysal pointed out that oxygen starvation in neoplastic cells is thought to promote malignant tumor formation. ¿The biological basis of this wider role,¿ he suggested, ¿is probably through oxygen sensing, because if this is defective in common solid tumors, those cancers tend to grow much more aggressively. It¿s defective for example,¿ he added, ¿in bladder, breast, cervical, stomach, lung, ovary, nasopharyngeal cancers and melanoma. These all show some sort of defect in the chromosome-11 region, where the gene that we found ¿ and report in today¿s Science ¿ is located.

¿That novel gene, SDHD, (succinate-ubiquinone-oxidoreductase), is mutated or missing in the genomes of paraganglioma families. The protein it expresses, cytochrome b small subunit, (CybS), ¿is probably an oxygen sensor,¿ Baysal and his co-authors propose.

The Pittsburgh team has been seeking that human SDHD gene ¿for the better part of five years.¿ Baysal recounted their quest: ¿Our approach was actually positional cloning. So we had no idea what sort of gene we were looking for. Eventually, we narrowed the critical region on chromosome 11 to 400 kilobases, a stretch that can still contain 10 genes ¿ because each gene on average spans 40,000 base pairs, and our critical region was 400,000 bps.

¿That meant,¿ he went on, ¿that there were other genes in the region. Because the literature suggested that mitochondria could be involved in oxygen sensing, and because we knew there was a mitochondrial gene in that region, we selected that gene. Both by positional cloning and what is sometimes called positional candidate approach,¿ he observed, ¿this was guilt by association. The fact that we figured out this oxygen-sensing connection facilitated the discovery.¿

He made the point that, ¿For the first time, we found a gene defect coding for a mitochondrial protein causing an inherited tumor. But the SDHD gene itself ¿ which sits on the long arm of chromosome 11 ¿ is not located in mitochondria. It¿s in the cell¿s nuclear genome. Mitochondria,¿ he explained, ¿has its own genome, but some of its proteins are actually encoded by the nuclear genomic DNA, because during evolution, some of those mitochondria genes migrated to the nucleus. SDHD is such a gene.¿

Rx: Mice First, PGL Patients Next, Then Cancer Victims

The co-authors have not yet tested their gene in animals. ¿The problem was,¿ Baysal noted, ¿that there wasn¿t an animal model for our disease until now. Now the gene discovery is opening the way for preclinical studies. One interesting question is that in our PGL patients, only one copy of SDHD is defective; the other is normal. But the normal copy is lost during tumor development in the CB.

¿What¿s going to happen,¿ he wonders, ¿if both maternal and paternal copies were defective in the germ line ¿ genetically? Would it be compatible with life? What sort of clinical picture would it give? These sorts of questions are very important,¿ Baysal pointed out, ¿and they will be addressed by mouse studies in the future. We have a Dutch collaborating group that will pursue it.¿

Looking to the long-range future, he foresees two clinical potentials:

¿PGL patients are going to benefit from this first. It may lead to a cure eventually by gene therapy, because they have a defective gene. SDHD can theoretically be introduced into their carotic-body cells. Right now preclinical diagnosis is possible for them. They can be screened more frequently, and precautions taken.

¿Secondly,¿ Baysal continued, ¿If we prove that this gene plays a role in common cancer, through oxygen sensing, then therapeutic modalities can be improved. One could introduce this gene locally to the tumor cell, and also employ hyperbaric oxygen therapy. If we can improve the oxygen sensing of the cancer cells, and prevent their malignant progression, this would be possible - provided our hypothesis of common cancer's involvement in oxygen sensing is proved."