Harvard Medical School Professor of Genetics Frederick W. Alt, a Howard Hughes Medical Institute investigator at Children’s Hospital Boston (Department of Molecular Medicine), has received the Clowes Memorial Award from the American Association for Cancer Research (AACR), acknowledging his three decades of seminal discoveries in genomic instability and cancer. The Clowes is the oldest award given by the AACR, and recognizes outstanding, recent accomplishments in basic cancer research.

The award was presented at the association’s 95th annual meeting in Orlando, Fla., on March 27-31. Alt, the Charles A. Janeway Professor of Pediatrics, also recently received the prestigious Scientific Leadership Award in Immunology from the Irvington Institute for Immunological Research in New York City.

Alt was the first to elucidate a molecular mechanism for genomic instability involved in promoting cancer. The human genome is at constant risk for mutations owing to environmental insults, errors in gene replication, and other factors that can cause chromosomes to break and bits of DNA to be lost, duplicated, or reshuffled to the wrong chromosomes (translocated). Cells have repair mechanisms that constantly fix this damage, but when the repair process breaks down, the genome becomes unstable and cancers are more likely to develop.

Alt’s wide-ranging research has important implications for cancer prevention and has sparked much additional research by other scientists. His work has touched on many aspects of genomic instability and cancer. Several key advancements specifically cited by the AACR are detailed below, followed by a description of Alt’s more recent work.

Gene amplification

Alt’s early work led to the discovery of a major form of genomic instability known as gene amplification. Studying how cancers become resistant to the chemotherapy drug methotrexate, Alt studied how cancer cells churn out high levels of an enzyme that enables the resistance. He showed that gene amplification endows these cells with many extra copies of the gene encoding this enzyme.

N-myc oncogene amplification

The gene amplification work led Alt to co-discover a specific cancer-causing gene, or oncogene, known as N-myc. He found that N-myc is frequently amplified in neuroblastoma, a childhood brain cancer, making the cancer especially aggressive. This discovery provided one of the first systematic associations with a particular tumor.

The nonhomologous DNA end-joining pathway

During the 1980s, Alt also turned his attention to immunology studies, examining how the immune system can recognize and defend against an almost infinite variety of attackers. This work also led to key discoveries about genomic instability.

Mechanisms of oncogene amplification and translocation

Alt’s lab also has demonstrated that when a cell is deficient in both end-joining proteins and a protein known as p53, gene amplification, translocations, and tumor formation are greatly enhanced.

New frontiers

Alt’s more recent work is exploring further mechanisms of genomic stability in cancer. One mechanism involves H2AX, a structural protein that helps ensure that double-strand DNA breaks are properly repaired by the end-joining proteins.

A second mechanism, again drawing on his work in immunology, is class-switch recombination. This gene-reshuffling tool is used by the immune system to instruct an antibody where to go in the body and what strategy to use in fighting a pathogen.