Epidemiologic Research of Rare Cancers: Trends, Resources, and Challenges.

Background: The goals of this project were to assess the status of NCI's rare cancer-focused population science research managed by the Division of Cancer Control and Population Sciences (DCCPS), to develop a framework for evaluation of rare cancer research activities, and to review available resources to study rare cancers.

Methods: Cancer types with an overall age-adjusted incidence rate of less than 20 cases per 100,000 individuals were identified using NCI Surveillance, Epidemiology and End Results (SEER) Program data. SEER data were utilized to develop a framework based on statistical commonalities.

DNA polymerase ζ-dependent lesion bypass in Saccharomyces cerevisiae is accompanied by error-prone copying of long stretches of adjacent DNA.

Translesion synthesis (TLS) helps cells to accomplish chromosomal replication in the presence of unrepaired DNA lesions. In eukaryotes, the bypass of most lesions involves a nucleotide insertion opposite the lesion by either a replicative or a specialized DNA polymerase, followed by extension of the resulting distorted primer terminus by DNA polymerase ζ (Polζ). The subsequent events leading to disengagement of the error-prone Polζ from the primer terminus and its replacement with an accurate replicative DNA polymerase remain largely unknown.

Fanconi-like crosslink repair in yeast.

Interstrand crosslinks covalently link complementary DNA strands, block replication and transcription, and can trigger cell death. In eukaryotic systems several pathways, including the Fanconi Anemia pathway, are involved in repairing interstrand crosslinks, but their precise mechanisms remain enigmatic. The lack of functional homologs in simpler model organisms has significantly hampered progress in this field.

Rad5-dependent DNA repair functions of the Saccharomyces cerevisiae FANCM protein homolog Mph1.

Interstrand cross-links (ICLs) covalently link complementary DNA strands, block DNA replication, and transcription and must be removed to allow cell survival. Several pathways, including the Fanconi anemia (FA) pathway, can faithfully repair ICLs and maintain genomic integrity; however, the precise mechanisms of most ICL repair processes remain enigmatic. In this study we genetically characterized a conserved yeast ICL repair pathway composed of the yeast homologs (Mph1, Chl1, Mhf1, Mhf2) of four FA proteins (FANCM, FANCJ, MHF1, MHF2).

A cancer-associated DNA polymerase delta variant modeled in yeast causes a catastrophic increase in genomic instability.

Accurate DNA synthesis by the replicative DNA polymerases alpha, delta, and epsilon is critical for genome stability in eukaryotes. In humans, over 20 SNPs were reported that result in amino-acid changes in Poldelta or Polepsilon. In addition, Poldelta variants were found in colon-cancer cell lines and in sporadic colorectal carcinomas.

Anc1, a protein associated with multiple transcription complexes, is involved in postreplication repair pathway in S. cerevisiae.

Yeast strains lacking Anc1, a member of the YEATS protein family, are sensitive to several DNA damaging agents. The YEATS family includes two human genes that are common fusion partners with MLL in human acute leukemias. Anc1 is a member of seven multi-protein complexes involved in transcription, and the damage sensitivity observed in anc1Delta cells is mirrored in strains deleted for some other non-essential members of several of these complexes.

Postreplication repair inhibits CAG.CTG repeat expansions in Saccharomyces cerevisiae.

Trinucleotide repeats (TNRs) are unique DNA microsatellites that can expand to cause human disease. Recently, Srs2 was identified as a protein that inhibits TNR expansions in Saccharomyces cerevisiae. Here, we demonstrate that Srs2 inhibits CAG .