Ancestry link to cancer molecular makeup

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Is there a connection between ancestry and the molecular makeup of cancers?

That’s a question that has hovered over cancer research since the completion of the Human Genome Project in 2003, and now a collaborative group known as the NCI Cancer Genome Analysis Network says it has some clues.

After studying a database including 10,678 patients and 33 cancer types, the researchers conclude that ancestry is tied to variations in hundreds of genes, but that the most important of these differences are linked to specific tissue types.

“This suggests that tracking the molecular effects of ancestry – both in normal and cancer tissue – needs to take a tissue-by-tissue approach,” says Rameen Beroukhim from the Dana-Farber Cancer Institute, US, co-senior author with colleague Andrew Cherniack of a paper in the journal Cancer Cell.

The researchers, from across North America and Europe, drew on data from The Cancer Genome Atlas (TCGA), and used a variety of molecular techniques to determine the ancestry of the patients whose tissue samples were analysed.

They classified patients as being primarily of European, East Asian, African, Native/Latin American, or South Asian descent. Those whose ancestry was at least 20% mixed were classified as being of admixed descent, then subcategorised.

The TCGA includes analysis of each patient’s tissue, having tested cancerous and normal cells for a range of molecular features.

These include mutations (miscopied sections of DNA), patterns of DNA methylation (a process that influences whether genes are switched on or off), messenger RNA (a molecule that carries a transcribed version of DNA and is indicative of gene activity) and microRNA (a form of RNA that assists or hampers gene activity).

Beroukhim and colleagues found that ancestry-associated differences spanned all of these features and were present in hundreds of different genes.

However, although ancestry affected molecular features in most cancer types, effects were not shared across cancer types. Molecular differences in lung cancers that were traceable to African ancestry, for example, were not found in breast, pancreatic or other cancers.

The researchers also found that ancestry-related features of normal cells carry over into the cancerous versions of those cells. “Most of the differences in the normal tissues of people with specific ancestries are recapitulated in cancer,” Beroukhim says.

And, he adds, the evidence suggests some of these differences may contribute to the development of certain cancers in people with similar backgrounds.

The researchers say they have yet to determine whether the molecular differences between ancestries result from environmental factors or genetic factors.

They conducted their initial analysis in patients whose ancestry was within one of the five genealogical groups then followed this with a similar analysis of data from the admixed populations.

“When the results of the two analyses jibed – when molecular differences specific to one ancestral group also appear in patients whose ancestry is a combination of that group and others – it was particularly strong evidence of the validity of the original finding,” says co-author Jian Carrot-Zhang, from Dana-Farber.

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