Genomic Instability in Familial Cancer Syndromes

University Of Tx Md Anderson Can Ctr, Houston TX

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Abstract

Chromosomal instability is a hallmark of human cancers, and tumors derived from individuals with Li-Fraumeni[unreadable] syndrome (LFS) often contain a multitude of aberrant chromosomes. Increasing evidence from human and[unreadable] mouse model systems suggests that proper maintenance of telomeres is important for chromosomal integrity[unreadable] and genome stability. Telomere dysfunction initiates the formation of the breakage-fusion-bridge cycle, leading[unreadable] to genome-wide alterations in gene dosage. In the setting of mutant p53, these diverse genetic alterations are[unreadable] hypothesized to fuel cancer initiation and progression. To test the hypothesis that the most common gain of[unreadable] function mutation in LFS (the p53R172H mutation corresponding to the p53R175H hotspot in human cancers) in the[unreadable] setting of telomere dysfunction promotes chromosomal instability and accelerates the onset of tumorigenesis in[unreadable] vivo, we have generated mice with normal or dysfunctional telomeres heterozygous or homozygous for the[unreadable] p53R172H mutation. We will compare the latency of tumor development, tumor spectrum, types of chromosomal[unreadable] aberrations observed, and telomere length of primary and established tumor cell lines between these four[unreadable] mouse cohorts. We will determine the presence of micro-satellite instability (MSI) in tumors derived from[unreadable] telomerase null mice to determine whether MSI is a hallmark of tumors where telomeres have been restored by[unreadable] a mechanism that involves alternative lengthening of telomeres.[unreadable] The clear generational impact of telomere dysfunction in the telomerase knockout mouse, coupled with exciting[unreadable] new data suggesting that the severity of the disease status in patients with dyskeratosis congenita correlates[unreadable] with progressive telomere shortening in later generations, implies that inheritance of short telomeres may be[unreadable] responsible for disease anticipation. We hypothesize that telomere dysfunction may be the basis for the earlier[unreadable] onset of cancers observed in descendents of affected LFS patients. We will test this hypothesis by isolating[unreadable] peripheral blood samples from parents and children of age and sex-matched controls and LFS families with[unreadable] different types of p53 mutations and determine the telomere length in these samples using flow-FISH,[unreadable] quantitative-FISH and terminal restriction fragment (TRF) length analyses. We anticipate that inheritance of[unreadable] short telomeres will lead to presentation of cancers at a younger age.[unreadable] Relevance: the proposed research has direct relevance to public health, since telomere length shortening may[unreadable] be a biomarker for overall genomic instability in patients with LFS. We believe that telomere dysfunction will[unreadable] prognosticate the early onset of tumors in patients with LFS. If this is true, then early diagnostic testing for[unreadable] average telomere lengths in LFS families will be extremely important. For example, LFS patients with very[unreadable] short telomeres may warrant more frequent monitoring for elevated cancer risk. In addition, emerging studies[unreadable] from other human diseases such as Dyskeratosis Congenita and Aplastic Anemia indicate that it is likely that[unreadable] telomere shortening may prognosticate elevated disease risk in the general population. It is therefore possible[unreadable] that telomere length determination may become standard medical practice in the near future.