DO CNVs and PT MUTATIONS ACCUMULATE IN THE SPERMATOGONIA OF OLDER MEN? PROSTATE CANCER RISK RISES WITH PATERNAL AGE, SO DOES SCHIZOPHRENIA AND AUTISM

But King said Sebat and Wigler, colleagues whom she kept referring to affectionately as "the boys," wanted to see if a disease such as autism, which occurs more sporadically, may arise through a different kind of genetic disorder -- by random errors of copying or duplication anywhere throughout the genome, rather than because of mutations of the same genes.

"It establishes a different paradigm for how we should look for the causes of autism," King said. More broadly, she said, it should prompt scientists to consider the role of CNVs in other diseases as well. With Sebat and Wigler, King and other UW colleagues are already looking at how CNVs may contribute to schizophrenia as well.

"Most cases of schizophrenia are also sporadic with no family history," said UW child psychiatrist Jack McClellan, who is working with King on the schizophrenia study. Sebat and Wigler's approach, McClellan said, holds the promise for solving this mystery as well.

Sebat, Wigler, King and their teams examined genetic material taken from 264 families: 118 families with a single autistic child, 47 families with multiple siblings who had autism and 99 families with no diagnoses of autism.

Rather than looking for a specific gene mutation, or a series of gene mutations, the entire genomes of the participants were analyzed for evidence of genetic mutations present in the children but not the parents.






Genome-wide association study reveals new genetic risk factor for prostate cancer
The post-genomic era has sparked a new trend in biomedical research that was scarcely imaginable a few years ago. Case in point: the NCI Cancer Genetic Markers of Susceptibility (CGEMS) project, a genome-wide association study that leverages knowledge from the Human Genome and HapMap projects, while capitalizing on the latest generation of DNA chip technologies.

Co-led by David Hunter, MD, professor of cancer prevention at HSPH and director of the DF/HCC High-Throughput Polymorphism Detection Core, CGEMS is a collaboration between the National Cancer Institute and several other institutions, which are pooling population resources to find the common inherited mutations that contribute to increased risk for prostate and breast cancer.



One such technology is array-based comparative genomic hybridization (aCGH), a technique using microarrays for screening DNA sequences across the genome to detect copy number aberrations: losses, gains, or amplifications, which are often associated with the development and progression of cancer. Mapping these gains and losses accurately can help pinpoint the genes implicated in cancer and provide powerful tools in diagnosis and prognosis.




Parental Age at Child's Birth and Son's Risk of Prostate Cancer: The Framingham Study.
Original Contributions

American Journal of Epidemiology. 150(11):1208-1212, December 1, 1999.
Zhang, Yuqing 1; Kreger, Bernard E. 1,2; Dorgan, Joanne F. 3; Cupples, L. Adrienne 4; Myers, Richard H. 1; Splansky, Greta Lee 5; Schatzkin, Arthur 3; Ellison, R. Curtis 1
Abstract:
The authors examined the relation of parental age at birth to the risk of prostate cancer among sons with the use of data from the Framingham Study. During 42 years of follow-up (1949-1993), 141 prostate cancer cases occurred in 2,164 men. All but six cases were confirmed by histologic report. The incidence rate of prostate cancer increased from 1.70 per 1,000 person-years among sons in the lowest quartile of paternal age (<27 years), to 2.00, 2.32, and 2.74 among those of each increased paternal age category (27-<32, 32-<38, and >=38 years), respectively. After adjustment for age and other covariates, men in the second, third, and oldest quartiles of paternal age had 1.2, 1.3, and 1.7 times increased risk of prostate cancer compared with men in the youngest quartile (p for trend = 0.049). Further adjustment for maternal age did not change the relation materially. The association of older paternal age with risk of early-onset prostate cancer (<65 years) appeared stronger than that with late-onset disease (>=65 years). No increased risk of prostate cancer was observed among subjects in the older maternal age category. The effect of increased paternal age on prostate cancer risk may operate through increased germ cell mutation rate or by mechanisms not yet defined.
Copyright 1999 by The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA. All rights reserved.

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The link between schizophrenia and older paternity had been made before, but this was the first large study to look at a range of factors that could confound the results, said Professor John McGrath, a psychiatric epidemiologist at the Queensland Centre for Mental Health Research.

"If all babies had fathers less than 30, the paper suggests, the incidence of schizophrenia would reduce by 15 per cent," he said.

In 2002 the average age of fathers was 32, compared with an average age of 29 in 1982, according to data from the Australian Bureau of Statistics.

The executive director of the mental health lobby group SANE Australia, Barbara Hocking, said the Swedish research, published in the British medical journal BMJ, was "major, major stuff".

She likened the research to the link between mothers over 35 and an increased risk of Down syndrome in their children. "It helps people understand what risk factors may be, so you can take action to reduce them."