How should we relate discoveries in one area of cancerresearch to those in another? Is the best characteriza-tion of a human cancer the activating mutation at its

origin, its spectrum of tumor suppressors subject to epigeneticinactivation, or the dominant deregulated signaling pathwayspromoting its proliferation? Many of these signaling pathwaysact in parallel and are organized into networks that behave inways that can only be adequately described by combiningmodels with experiments. It is time to coordinate our analysiswithin a systematic setting.

To find universal principles, one must first collect a lot ofdata; on page 331, that is what Felix Mitelman and colleaguesdid. They analyzed published reports of 44,750 cytologicallyabnormal neoplasms and concluded that solid tumors canresult from much the same translocational gene rearrange-ments and gene fusions that initiate leukemias and lym-phomas. They found considerable overlap in the set of cellularfunctions affected. But they also recognize that it is difficult tostudy karyotypes in solid tumors, and in those, a multitude ofsubsequent traces of genome instability mask a commonalityof mechanism.

Addressing how tumors progress, Hiromu Suzuki and col-leagues (page 417) found that epigenetic silencing of the SFRPgenes that encode secreted antagonists of the Wnt signalingpathway is an early event in colorectal tumors. As Mark Taketopoints out in his News and Views on page 320, they also foundthat the activity of the pathway could be modulated by SFRPs,even in the presence of constitutive Wnt signaling resultingfrom mutations in downstream components of the pathway.

This result illustrates just how far cancer research hasadvanced, as mutations with residual function would havecomplicated the first genetic dissection of the signaling path-way. Here, they offer the hope of therapeutically reactivatingthe function that remains.

In the right context, determining the limitations of an anti-cancer strategy is as informative as proving its utility. Here,Dmitry Bulavin and colleagues on page 343, were able to inhibitmammary carcinogenesis resulting from overexpression ofcyclin D1 by removing the Wip1 phosphatase from mice. Sometumors escaped this restriction, and these had gained a down-stream block: epigenetic silencing of the p16 tumor suppressor.Removing Wip1 did not prevent induction of tumorigenesis bythe separate pathway involving constitutive Wnt signaling.

Looking at these results, it is irresistible to wonder about theeffects of SFRPs on breast cancers with a deregulated Wntpathway. These studies relate to questions of even larger com-pass. Comparison of the genomic profiles of tumor suppressorgenes silenced by methylation in human breast and colon can-cer will be a big step in the scope of cancer epigenetics.Whether the sequence in which cancer mutations or epigeneticsilencing events occur is part of the selective forces that shapeprogression and remission, and whether this sequence is inde-pendent of their action upstream or downstream in a sequenceof gene actions, are important general problems.

The further challenge, outlined in the quote above, is to fitreductive research findings from different areas into the physi-ology of the affected individuals. The National CancerInstitute’s Cancer Genome Anatomy project (http://cgap.nci.nih.gov) has made a strong start in this direction, by linkingtogether much of the available mutation and pathway informa-tion together through the annotated human genome. Buildingon this organized information, it will eventually be possible tochoose combinations of therapies specific to a set of geneticallyaltered pathways that will steer a tumor toward its elimination.

E D I T O R I A L

Intersecting paths to cancer

NATURE GENETICS VOLUME 36 | NUMBER 4 | APRIL 2004 313

The amount of information becoming available on the biology andgenetics of human tumors is staggering. The challenge now is tointegrate these diverse data with information on clinical behavior,pathology, drug response, deregulated pathways and processes.—Donna Albertson and colleagues, Nat. Genet. 34, 369–376 (2003).

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