Nasopharyngeal carcinoma as a paradigm of cancer genetics.

The unusual incidence patterns for nasopharyngeal carcinoma (NPC) in China, Northeast India, Arctic Inuit, Peninsular and island Southeast Asia, Polynesian Islanders, and North Africans indicate a role for NPC risk genes in Chinese, Chinese-related, and not-obviously Chinese-related populations. Renewed interest in NPC genetic risk has been stimulated by a hypothesis that NPC population patterns originated in Bai-Yue / pre-Austronesian-speaking aborigines and were dispersed during the last glacial maximum by Sundaland submersion. Five articles in this issue of the Chinese Journal of Cancer, first presented at a meeting on genetic aspects of NPC [National Cancer Center of Singapore (NCCS), February 20-21, 2010], are directed towards incidence patterns, to early detection of affected individuals within risk populations, and to the application of genetic technology advances to understanding the nature of high risk. Turnbull presents a general framework for understanding population migrations that underlie NPC and similar complex diseases, including other viral cancers. Trejaut et al. apply genetic markers to detail migration from East Asia through Taiwan to the populating of Island Polynesia. Migration dispersal in a westward direction took mongoloid peoples to modern day Northeast India adjacent to Western China (Xinjiang). NPC incidence in mongoloid Nagas ranks amongst the highest in the world, whereas elsewhere in India NPC is uncommon. Cao et al. detail incidence patterns in Southeast China that have occurred over recent decades. Finally, Ji et al. describe the utility of Epstein-Barr virus serostatus in early NPC detection. While genetic risk factors still remain largely unknown, human leukocyte antigen (HLA) genes have been a focus of attention since the discovery of an HLA association with NPC in 1973 and, two years later, that NPC susceptibility in highest-risk Cantonese involved the co-occurrence of multi-HLA locus combinations of HLA genes as chromosome combinations, or haplotypes (e.g. HLA-A2-B46), whereas in relatively lower-risk non-Cantonese Chinese (Hokkiens, Teochews) they appeared to act independently, a strength of association reflecting the 30-50-fold difference in incidence between highest risk Cantonese and lowest-risk Indians. The prototypic haplotype HLA-A2-B46 extends over megabases. An upstream DNA segment (near HLA-DPA1), has close similarity to Gorilla, with no obvious homology to Chimpanzee in current databases, suggesting that a reticulate model of primate evolution may be more appropriate than simple phylogeny. The DNA variation level in this segment is high enough for it to be a hominin remnant. HLA-B46 arose in mongoloids and remains largely limited to Chinese so the question arises as to whether the hominin candidate segment indicates an eastward trek of Homo neanderthalensis or the survival of much earlier Homo erectus? In 2011 sequencing technologies have finally caught up with the requirement to separate parental haplotypes. Recently achieved chromosome separation for whole genome di-haploid genetic and epigenetic analysis of parental inheritance in single individuals will reveal interacting patterns of multi-locus haplotypes as humans move in and through successive environments, thus providing definitive information on the genetic affinities between extant populations, and of the migrations that have led to the global distribution of modern Homo. The challenge can now be met of seeking HLA-associated locations both within and outside the HLA complex on each of the pair of chromosomes. More broadly, for every disease, genetic risk detection will require resolution of the diploid genome as a di-haplome. In the context of NPC, HLA genetic risk complete autosomal di-haplomic sequencing will enable testing of the Wee unitary origin hypothesis of NPC risk even among populations with no apparent mongoloid affinity.

Nasopharyngeal carcinoma in the Northeastern states of India.

Nasopharyngeal cancer (NPC) is a rare disease in most parts of the world, except for Southeast Asia, some parts of North Africa and the Arctic. It is mostly seen in people of Chinese origin. In India, NPC is also rare, except for the Hill States of Northeast India, particularly Nagaland, Manipur, and Mizoram. The striking feature of NPC in Northeast India is that the incidence ranges over the complete spectrum from the lowest (as 0.5/100 000 to 2.0/100 000 among Caucasoid) to the highest (as about 20/100 000 among Cantonese/Zhongshan dialect Chinese). The age-adjusted rate of NPC in Kohima district of Nagaland State is 19.4/100 000, which is among the highest recorded rates. By contrast, in Assam, one of the so-called Hill States but not itself a hilly state, NPC is much less common. The Northeastern region is distinguished by a preponderance of the Tibeto-Burman languages and by variable mongoloid features among peoples of the region. The nature of the migratory populations who are presumed to be bearers of the mongoloid risk is unknown, but these NPC occurrence features provide an outstanding opportunity for NPC risk investigation, such as that of the hypothesis of Wee et al. for westward displacement of Chinese aborigines following the last glacial maximum.

The prevalence and prevention of nasopharyngeal carcinoma in China.

Nasopharyngeal carcinoma (NPC) has remarkable epidemiological features, including regional, racial, and familial aggregations. The aim of this review is to describe the epidemiological characteristics of NPC and to propose possible causes for the high incidence patterns in southern China. Since the etiology of NPC is not completely understood, approaches to primary prevention of NPC remain under consideration. This situation highlights the need to conduct secondary prevention, including improving rates of early detection, early diagnosis, and early treatment in NPC patients. Since the 1970's, high-risk populations in southern China have been screened extensively for early detection of NPC using anti-Epstein-Barr virus (EBV) serum biomarkers. This review summarizes several large screening studies that have been conducted in the high-incidence areas of China. Screening markers, high-risk age range for screening, time intervals for blood re-examination, and the effectiveness of these screening studies will be discussed. Conduction of prospective randomized controlled screening trials in southern China can be expected to maximize the cost-effectiveness of early NPC detection screening.

Genomics, morphogenesis and biophysics: triangulation of Purkinje cell development.

The cerebellar Purkinje cells (P-cells) comprise an organelle that is suitable for combined analysis by morphology and genomics, using biophysical tools. In some unknown way, genomic information specifies the development of P-cells. One of us (AJP) has previously proposed that fractal processes associated with DNA are in a causal relation to the fractal properties of organelles such as P-cells (FractoGene, 2002, patent pending). This fractal postulate predicts that the dendritic arborization of P-cells will be less complex in lower order vertebrates. The prediction can be tested by systematic comparative neuroanatomy of the P-cell in species for which genome sequences permit inter-species comparison. The Fugu rubripes (Fugu), Danio rerio (Danio) and other species are lower order vertebrates for which genome sequences are available and tests could be conducted. Consistent with the fractal prediction, P-cell dendritic arbor is primitive in Fugu, being much less complex than in Mus musculus and in Homo sapiens. Genomic analysis readily identified PEP19/Pcp4, Calbindin-D28k, and GAD67 genes in Fugu and in Danio that are closely associated with P-cells in Canis familiaris, Rattus norvegicus, Mus musculus and Homo sapiens. Gene L7/Pcp2 exhibits strongest association with P-cells in higher vertebrates. L7/Pcp2 shows strong protein residue homology with genes greater than 600 residues and including 2-3 GoLoco domains, designated as having G protein signaling modulator function (AGS3-like proteins). Fugu has a short gene with a single GoLoco domain, but it has greatest homology with the AGS3-like proteins. No similar short gene is present in Danio or in Xenopus. Classical L7/Pcp2 is only detected in higher vertebrates, suggesting that it may be a marker of more recent evolutionary development of cerebellar P-cells. We expect that a new generation of data mining tools will be required to support recursive fractal geometrical, combinatorial, and neural network models of the genomic basis of morphogenesis.