Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.

were included from 14 Surveillance, Epidemiology, and End Results (SEER) Program state and regional population-based cancer registries covering 54% of the U.S. API population. Cancer deaths were included from the seven states that report death information for detailed API groups and which cover over 68% of the total U.S. API population. Using detailed racial/ethnic population data from the 2000 decennial census, we produced incidence rates centered on the census year for Asian Indians/Pakistanis, Chinese, Filipinos, Guamanians, Native Hawaiians, Japanese, Kampucheans, Koreans, Laotians, Samoans, Tongans, and Vietnamese. State vital records offices do not report API deaths separately for Kampucheans, Laotians, Pakistanis, and Tongans, so mortality rates were analyzed only for the remaining API groups. Results Overall cancer incidence rates for the API groups tended be lower than overall rates for non-Hispanic whites, with the exception of Native Hawaiian women (All cancers rate = 488.5 per 100,000 vs. 448.5 for non-Hispanic white women). Among the API groups, overall cancer incidence and death rates were highest for Native Hawaiian and Samoan men and women due to high rates for cancers of the prostate, lung, and colorectum among Native Hawaiian men; cancers of the prostate, lung, liver, and stomach among Samoan men; and cancers of the breast and lung among Native Hawaiian and Samoan women. Incidence and death rates for cancers of the liver, stomach, and nasopharynx were notably high in several of the API groups and exceeded rates generally seen for non-Hispanic white men and women. Incidence rates were lowest among Asian Indian/Pakistani and Guamanian men and women and Kampuchean women. Asian Indian and Guamanian men and women also had the lowest cancer death rates. Selected API groups had less favorable distributions of stage at diagnosis for certain cancers than non-Hispanic whites. Conclusions Possible disparities in cancer incidence or mortality between specific API groups in our study and non-Hispanic whites (referent group) were identified for several cancers. Unfavorable patterns of stage at diagnosis for cancers of the colon and rectum, breast, cervix uteri, and prostate suggest a need for cancer control interventions in selected groups. The observed variation in cancer patterns among API groups indicates the importance of monitoring these groups separately, as these patterns may 123Cancer Causes Control (2008) 19:227-256 DOI 10.1007 provide etiologic clues that could be investigated by analytic epidemiological studies.