Genetic Loci Prone to Homozygosity Linked to Carcinomas

By Karla Gale

NEW YORKMAR 25, 2008 (Reuters Health) - Homozygosity at certain "hot spot" gene locations appears to play an important role in cancer susceptibility, scientists at the Cleveland Clinic Foundation report in the Journal of the American Medical Association for March 26.

"This is a paradigm-shifting study that yielded data suggesting a novel mechanism of predisposition to common cancers," senior author Dr. Charis Eng told Reuters Health. "This type of cancer predisposition does not affect a small number of people (as do BRCA1/2, etc), but affects populations."

According to the Ohio-based research team, they had been researching loss of heterozygosity/allelic imbalance (LOH/AI) in cancer tissues when they "anecdotally observed a low frequency of germline heterozygosity in cancer patients compared with controls."

To explore this association, Dr. Eng"s group studied germline and corresponding tumor DNA isolated from 385 patients with invasive carcinomas (147 breast, 116 prostate, and 122 head and neck squamous cell carcinomas) using 345 autosomal microsatellite markers.

They found that 16 loci had higher-than-predicted frequencies of germline homozygosity in each of the three groups of patients.

Among cancer patients who were germline heterozygous at those 16 loci, the frequency of LOH/AI was significantly increased at those same sites in the corresponding carcinomas (p < 0.001).

"Many of the hot spot loci encompass several genes," Dr. Eng noted. "Some include tumour suppressor genes within, but not always."

The research team obtained similar results when analyzing a publicly available set of paired germline and tumor DNA from 205 patients with lung carcinoma.

"Furthermore," they state, "we have shown that this observation can be generalizable; ie, the more frequent the homozygosity at any given locus, the more LOH/AI can be found at those loci in the tumors of cancer patients that happened to be heterozygous in the germline."

The researchers propose that the hot spot loci they identified represent common fragile sites with increased sensitivity to DNA damage.

These observations "link the somatic and germline cancer genetic fields" and further the understanding of the mechanisms underlying carcinogenesis "tremendously," Dr. Eng said. "The next question is, is this type of low penetrance cancer predisposition applicable to all types of malignancies - and most importantly, why?"

She concluded: "If validation by other groups and perhaps using other types of cancers occurs repeatedly, then this type of genetic testing may be added to the routine clinical armamentarium of cancer risk assessment tools in the near future."

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