If Shakespeare were alive today, he might well be writing his "sevenages of man" more in tune with society's contemporary concerns forhealth and longevity. To wit: the infant (sudden infant deathsyndrome); the schoolboy (acne); the lover (AIDS-testing); the soldier(wound-healing); the justice (cardio-fitness); the foolish old man(prostate check-up); the seventh and last age (non-Hodgkin'slymphoma).Not only is non-Hodgkin's lymphoma (NHL) afflicting more people asthey grow older, "it is the third most rapidly increasing cancer in theU.S. population," molecular biologist Gino Cortopassi told BioWorldToday while discussing his paper in today's Proceedings of theNational Academy of Sciences (PNAS).Cortopassi, who teaches molecular pharmacology and toxicology at theUniversity of Southern California School of Medicine, observed thatfor lung cancer and melanoma, the two malignancies rising even fasterthan NHL, "we know the cause. But why NHL is escalating as it is, isstill a mystery."He made the point that "someone who is 80 years old has 50 times therisk of getting NHL as does a child of five. Like most other cancers, itgoes up very fast with advancing age."Thus, in 1991, more than 37,000 cases of NHL were diagnosed in theU.S. and almost 19,000 deaths recorded. These were not sudden deaths.Between diagnosis and demise, a patient may live with his or herdisease for perhaps five to eight years.When The Immune System Messes UpLymphomas are cancers of the lymphoid tissue, mainly in the lymphnodes. These produce the body's B lymphocytes, the white blood cellsthat generate the immune-system's antibodies for counterattackinginvading antigens. To take on every antigen imaginable, B cells fashionspecific molecules, each shaped to clutch and cope with a tight-fittingantigen.To perform this task of almost infinite diversity, three sets of genescooperate, under the management of an enzyme called VDJrecombinase. Besides raising up armies of precisely tailored antibodies,this process also equips T cell receptors with active-site opponents ofpathogens and other antigenic enemies.In the human immune system, because to err is human, the VDJenzyme complex sometimes misses a beat. In the case of NHL, itcleaves two of the body's 46 chromosomes, numbers 14 and 18, andswaps some of their DNA. This chromosomal translocation mutates agene, BCL2, which controls programmed cell death -- apoptosis. Thatis, it gets rid of B cells that have outlived their usefulness, either bydamage or senescence. (BCL stands for B cell lymphoma gene.)As a result, the immortalized B cells live on, forever dividing, bringingon lymphoma. These are somatic mutations, Cortopassi emphasizes.Unlike many genetically inherited chromosomal anomalies, these, hespeculates, happen as a reaction to some antigenic, environmental,insult. So when a single B cell mutates at the BCL2 oncogene, all of itsprogeny follow suit, and the clone proliferates into a tumor in spleen,lymph node and blood.Cortopassi's report in today's PNAS bears the foreboding title, "BCL2translocation frequency rises with age in humans." As with all PNASpapers, it had to be sponsored by a member of the Academy, in thiscase molecular biologist Philip Hanawalt of Stanford University. Hetold BioWorld Today that "I communicated Cortopassi's veryimportant, seminal work for PNAS publication because it shows thatthe older we get, the greater our chance of getting cancer."In fact, Hanawalt added, "If we live to be 100, we'll probably die ofcancer. "Heavy Smoking Triples NHL RiskHe explained that it requires a number of steps, five to a dozen or so,for a cell to go from normal to malignant. "We are gradually learningwhat these steps are," Hanawalt observed, "and the important feature ofCortopassi's work is that it shows a change in the process toward aparticular type of cancer, namely lymphoid hyperplasia, a changefound in older people."Cortopassi stated that "age is the single most significant risk factor incancer, and the incidence of most cancers rises exponentiallythroughout human life." He noted that "in the rise of NHL, this is notjust because the population is living longer." In work not yet published,he and his co-authors have determined that "persons who are heavysmokers are at two or three times increased risk for non-Hodgkin'slymphoma. They also have about a three-fold increase in the BCL2mutation in their lymphocytes."He pointed out that an accumulation of mutations in oncogenes overthe course of human life has long been proposed to explain the higherrisk of cancer in the elderly. "This has never been directlydemonstrated until now," he stated.The researchers devised a nested polymerase chain reaction assay tolook for translocation mutations in the spleen and blood of 53 livingpersons and 31 autopsies, none of whom had NHL. They found that theBCL2 mutations were 40 times higher in individuals over 60 than inthose under 20 years of age. In the autopsied spleens, the frequency oftranslocated chromosomes varied from less than one per million cellsto 853 per million.In an autopsied fetus, the rate was zero, underlining the somatic, ratherthan germline, origin of the mutation. Translocation frequency rosemarkedly after 30 years of age, compared with under 29 years.Sampling the blood of the living subjects at intervals revealed that therogue clones of mutant oncogenes persisted over time, a finding thatconfirmed their predicted role as inhibitors of cell death. n

-- David N. Leff Science Editor

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