Mitochondrial mutations and rearrangements as a diagnostic tool for the detection of sun exposure, prostate cancer and other cancers

Abstract

Mitochondrial DNA deletions useful for the detection of cancers and sun exposure are provided. In particular, methods and kits for detecting mitochondrial DNA deletions for the early detection, diagnosis and progression of prostate cancer, sun exposure and non-melonoma skin cancer are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation of U.S. application Ser. No. 11 / 975,390, filed 18 Oct. 2007, which is a Continuation of PCT Application number PCT / CA2006 / 000652, filed 18 Apr. 2006, which claims priority from US Provisional applications: 60 / 789,872, filed 7 Apr. 2006; 60 / 721,522, filed 29 Sep. 2005; and 60 / 672,016, filed 18 Apr. 2005. The entire contents of the aforementioned related applications is incorporated herein by reference.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to the field of mitochondrial genomics. In particular it is related to mutations and rearrangements in the mitochondrial genome and their utility as an indicator of sun exposure, aging, and the genesis or existence of disease, for example detecting the presence of pre-neoplasia, neoplasia and progression towards potential malignancy before common clinical symptoms are evident.BACKGROUND OF THE INVENTION[0003]The current mega-trend in the biologi...

AI Technical Summary

Problems solved by technology

However, there is an exceptional limitation to the use and implementation of this information as the data is not specific at the level of the individual.

The staggering complexity of the human genome makes application on an individual basis impractical.

It is well known that aging and specific types of pathology can alter, or mutate mtDNA compromising the energy production capacity of the cell.

This theory is plausible because not only is the mitochondrial genome lacking protective histones, but also is vulnerable to oxidative damage being found near the oxygen generating inner mitochondrial membrane.

Moreover, as mtDNA has a compact genome and lacks introns, deleterious events are thus likely to affect a coding sequence resulting in a biochemical dysfunction.

This dysfunction will further increase cellular oxidative stress which will lead to nuclear as well as mtDNA damage, thereby increasing the potential for a cell to enter into the cancer process (Penta et al., 2001).

1992) leading to eventual cell death.

However, mutations at these sites were not found to be associated with prostate cancer.

Moreover, through time, mitochondrial sequence loses integrity.

Moreover, sequencing the entire complement of mtDNA was a laborious task before the recent advent of high capacity, high-throughput robotic DNA sequencing systems.

In addition, population geneticists were able to gather significant data from two highly variable areas in the control region; however, these small regions represent a small portion of the overall genome, less than 10%, meaning that 90% of the discriminating power of the data is left unused.

BCCs are locally invasive and can cause significant morbidity but rarely metastasis.

SCCs show significant metastatic potential and the occurrence of multiple NMSCs in patients with immunosuppression causes significant management problems (Rees, 1998).

This is because the mitochondrial genome is particularly susceptible to mutations due to the high amounts of ROS produced in this organelle coupled with the lack of protective histones and a low rate of mtDNA repair (Pascucci et al.

However, these studies have not addressed population-level variation in mtDNA sequences in association with particular skin types and / or hair colour.

One of the questions which remains largely unanswered by the recent studies of mtDNA mutations in human tumours is the incidence of deletions of the mitochondrial genome in relationship to these tumours.

Firstly, due to technical limitations, it is not clear whether the mtDNA mutations are truly homoplasmic, as varying levels of heteroplasmy may indicate important disease transitions as well (Habano et al.

In addition, deletions are difficult to characterize.

Unfortunately, some early tumours are impossible to identify during rectal exams.

1995); however, this technique measures chromosomal changes that are only apparent in later stages of cancer development and is not sufficiently sensitive for the detection of minor alterations in DNA structure or chromosomal inversions, or reciprocal trans-locations in early cancers.

If some prostate cancers are polygenic, then mtDNA becomes an important diagnostic tool since it may be difficult to identify and understand the interplay between all associated nuclear genes in such cases.

Certainly, a key issue in prostate cancer research is to identify molecular markers that can effectively determine and distinguish tumour progression.

However, previous studies have been exclusively cross-sectional as they have not considered the clonal nature of mtDNA in maternal lines.

Aging research has been limited to this common deletion and polymorphisms in the control region.

Oxygen free radicals, a normal by product of ATP production, are a probable cause of this deletion, which increases in frequency with age.

1992) resulting in eventual cell death in old age.

Researchers have not yet determined this rate, which requires evaluation of population data through maternal lines.

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