Genetic susceptibility in a region of chromosome 9
CEA
These studies, published online in Nature Genetics on 5 July 2009, shed new light on the underlying mechanisms triggering various different cancers by characterizing a series of genetic determinants, some common to these cancers and some that are cancer-specific. This work can not only help improve targeted cancer prevention and screening strategies but also opens new therapeutic and diagnostic perspectives, particularly for diagnostic tools that can be re-geared for tracking cancer treatment response, and for novel therapeutic approaches. Identification of the genome regions involved in genetic predisposition to cancer and multifactorial diseases in general is one of the major challenges for genetics today.
The genetic study of melanoma published in Nature Genetics has investigated 300,000 genetic variants genome-wide and validated the results in a total sample of more than 10,000 people (2,500 subjects for the French strand) by comparing those who developed melanoma and those who did not. The study highlighted three regions. The first two found associated with melanoma are located on chromosomes 11 and 16 and include genes known to be involved in the pigmentation process. The third region found on chromosome 9 (9p21) harbours genes involved in the cell cycle and is associated not only with melanoma but also nevus count, as reported by a study on UK and Australian twins published in the same issue of Nature Genetics, as well as other cancers.
Interestingly, the genetic variants identified across the genome that are associated with melanoma risk show remarkable homogeneity of effect across populations of European ancestry living at different latitudes.
As underlined by Florence Demenais, genetic epidemiologist specializing in multifactorial disease and Head of the Inserm–Université Paris 7 Research Unit 946 at St Louis Hospital, the mechanisms governing the combined effects of genetic factors and sun exposure that cause melanoma are still poorly understood, but international-scale genome-wide association studies can provide key insights into the complex mechanisms underlying melanoma and further the development of new therapeutic targets geared to the molecular mechanisms.
To identify the genetic variants associated with glioma risk, the scientists performed a meta-analysis of two genome-wide association studies across a sample population of 5,540 people by comparing glioma patients against healthy subjects. Validation of results was obtained in three independent series from France, Germany and Sweden. The French cohorts represented over half the total number of subjects (5,408 subjects) involved in the validation study. This work led to identification of genetic variants located in the same region (9p21) as cutaneous melanoma, plus five additional regions on chromosomes 5, 8, 11 and 20. These results demonstrate for the first time that commonly-found genetic variations contribute to risk of glioma. The identification of chromosomal regions that include genes playing a role in cell division and cell death can now guide further exploration into the biological mechanisms causing primary brain tumours.
Taken together, this research illustrates the power of high-throughput genomics studies, as carried out in France at the CEA-CNG, which are capable of screening thousands of genome-wide genetic markers in thousands of subjects to identify genetic susceptibilities to diseases like cancer, which are a major public heath issue.
These studies form part of the national cancer genomics programme launched and funded by the INCa (National Cancer Institute) and led in tight collaboration with the CEA’s National Genotyping Centre (‘CNG’) and the Fondation Jean Dausset-CEPH human polymorphism study centre, alongside research teams from the French Institut Thématique Multi-organismes Cancer, and syndicated by the cancer research platforms.
The French strand of the melanoma and glioma research programmes was also partly funded by the French national anti-cancer league (‘LNCC’) and the French hospitals-coordinated clinical research program.
• Melanoma
Melanoma is the skin cancer that is most life-threatening, and over the last few decades the incidence of new cases of melanoma in Caucasian populations has continued to increase inexorably. There is strong inter-country variation in the incidence of melanoma due to the interplay between skin colour and exposure to sunlight. The incidence rates in France, at 9.5 cases per 100,000 women and 7.6 cases per 100,000 men, are mid-range for Europe, where fairer-skinned Scandinavian populations record higher melanoma rates than darker-skinned Mediterranean populations. Cutaneous melanoma is ranked 18th cause of cancer deaths.
Melanoma is a multifactorial disease, with two groups of factors: intrinsic and environmental. The major environmental risk factor is sun exposure, especially when intense, intermittent, and occurring during childhood. Pigmentation features such as red or blond hair, fair skin and light eyes together with a high number of moles (measured as a ‘nevus count’) increase the risk for melanoma, and like melanoma itself, they are influenced by genetic factors. Future studies should elucidate whether the genetic variants identified mainly influence the onset of melanoma via pigmentation features and nevus count or whether individual variants have a more direct impact on risk for melanoma.
• Glioma
Glioma accounts for around 80% of malignant primary brain tumours. In France, there are around 3000 new cases of glioma every year. Most gliomas are life-threatening, and glioma is ranked third-leading cause of death in young adults. Glioma, like any cancer, appears to have multifactorial genetic and environmental causes. Excluding the relatively few cases of radiation-induced glioma and the rare but well-characterized genetic forms, little is known – even today – of what causes these tumours.