Methods and Compositions for Identifying Global Microsatellite Instability and for Characterizing Informative Microsatellite Loci

A method of identifying an increased risk of developing a disease, comprising:

• obtaining a sample of nucleic acid from a subject;
• determining the sequence length of at least one informative microsatellite locus in said sample;
• and
• comparing the sequence length of the at least one informative microsatellite locus in said sample from the subject to a distribution of sequence lengths of the at least one informative microsatellite locus in nucleic acid obtained from a reference population of individuals identified as not having the disease;
• wherein, if the sequence length of the at least one informative microsatellite locus in said sample differs from the average sequence length of the at least one informative microsatellite locus in nucleic acid obtained from the disease-free reference population, then the subject is identified as being at an increased risk of developing the disease;
• wherein the at least one informative microsatellite locus was previously identified by a method comprising:
• (i) determining a distribution of sequence lengths for a plurality of microsatellite loci in nucleic acid obtained from a population of individuals identified as having the disease;
• (ii) determining a distribution of sequence lengths for a plurality of microsatellite loci in nucleic acid obtained from a population of individuals identified as not having the disease;
• (iii) comparing the distribution of sequence lengths for a first microsatellite locus in nucleic acid obtained from the disease population set forth in (i) to the distribution of sequence lengths for the same first microsatellite locus in nucleic acid obtained from the disease-free population set forth in (ii);
• (iv) repeating the comparing step (iii) for additional microsatellite loci;
• and
• (v) classifying as informative, any microsatellite locus whose distributions of sequence lengths do not significantly overlap between the population of individuals identified as having the disease and the population of individual identified as not having the diseases.

A method of identifying an increased risk of developing cancer, comprising:

• obtaining a sample of nucleic acid from a subject;
• determining the sequence length of at least one informative microsatellite locus in said sample;
• and
• comparing the sequence length of the at least one informative microsatellite locus in said sample from the subject to a distribution of sequence lengths of the at least one informative microsatellite locus in nucleic acid obtained from a reference population of individuals identified as not having cancer;
• wherein, if the sequence length of the at least one informative microsatellite locus in said sample differs from the average sequence length of the at least one informative microsatellite locus in nucleic acid obtained from the cancer-free reference population, then the subject is identified as being at an increased risk of developing cancer;
• wherein the at least one informative microsatellite locus was previously identified by a method comprising:
• (i) determining a distribution of sequence lengths for a plurality of microsatellite loci in nucleic acid obtained from a population of individuals identified as having cancer;
• (ii) determining a distribution of sequence lengths for a plurality of microsatellite loci in nucleic acid obtained from a population of individuals identified as being cancer-free;
• (iii) comparing the distribution of sequence lengths for a first microsatellite locus in nucleic acid obtained from the cancer population set forth in (i) to the distribution of sequence lengths for the same first microsatellite locus in nucleic acid obtained from the cancer-free population set forth in (ii);
• (iv) repeating the comparing step (iii) for additional microsatellite loci;
• and
• (v) classifying as informative, any microsatellite locus whose distributions of sequence lengths do not significantly overlap between the population of individuals identified as having cancer and the population of individuals identified as being cancer-free.

A method of evaluating the aggressiveness of a particular tumor type in a subject, comprising:

• obtaining a sample of nucleic acid from a subject;
• determining the sequence length of at least one informative microsatellite locus in said sample;
• and
• comparing the sequence length of the at least one informative microsatellite locus in said sample from the subject to a distribution of sequence lengths of the at least one informative microsatellite locus in nucleic acid obtained from (i) a population of individuals identified as having an aggressive tumor of the particular tumor type or (ii) a population of individuals identified as having a non-aggressive tumor of the particular tumor type;
• wherein, (i) if the sequence length of the at least one informative microsatellite locus in said sample from the subject differs from the average sequence length of the at least one informative microsatellite locus in nucleic acid obtained from the population of individuals identified as having an aggressive tumor, then the subject is identified as having a non-aggressive or (ii) if the sequence length of the at least one informative microsatellite locus in said sample from the subject differs from the average sequence length of the at least one informative microsatellite locus in nucleic acid obtained from the population of individuals identified as having a non-aggressive tumor, then the subject is identified as having an aggressive tumor.

A method of identifying a subject at increased risk for developing ovarian cancer, comprising:

• obtaining a sample from a subject;
• extracting nucleic acid from the sample;
• analyzing the nucleic acid in said sample from the subject to determine the sequence length of at least four microsatellite loci selected from the group consisting of loci 1-100 listed in Table 4;
• and
• comparing the sequence length of the at least four microsatellite loci in said sample from the subject to a distribution of sequence lengths of each of the at least four microsatellite locus in nucleic acid obtained from a reference population of individuals identified as not having ovarian cancer;
• wherein, if the sequence length of each of the at least four microsatellite loci in said sample from the subject differs from the average sequence length of the at least four microsatellite loci in nucleic acid obtained from the reference population, then the subject is identified as being at an increased risk of developing the ovarian cancer;
• wherein the method provides a sensitivity of at least 40% and a specificity of at least 90% for identifying subjects at increased risk of developing ovarian cancer.

A method of identifying a subject at increased risk for developing breast cancer, comprising:

• obtaining a sample from a subject;
• extracting nucleic acid from the sample;
• analyzing the nucleic acid in said sample to determine the sequence length of a microsatellite locus, wherein the locus is located in the CDC2L1/2 gene;
• and
• comparing the sequence length of the microsatellite locus in said sample to a distribution of sequence lengths of the microsatellite locus in nucleic acid obtained from a reference population of individuals identified as not having breast cancer;
• wherein, if the sequence length of the microsatellite loci in said sample differs from the average sequence length of the microsatellite locus in nucleic acid obtained from the reference population, then the subject is identified as being at an increased risk of developing the breast cancer;
• wherein the method provides a sensitivity of at least 90% and a specificity of at least 90% for identifying subjects at increased risk of developing breast cancer.

A method for measuring propensity for polymorphism, comprising:

• (a) iteratively aligning a set of microsatellite data corresponding to a subject in a population, to a reference microsatellite loci dataset, comprising:
• (i) iteratively selecting a microsatellite and sequence portions flanking the selected microsatellite from said set of microsatellite data corresponding to the said subject;
• and
• (ii) identifying a similarity between the selected microsatellite and sequence portions and a first locus from said reference microsatellite loci dataset;
• (b) iteratively determining sequence lengths of the microsatellite loci to which similarities were identified from said set of microsatellite data corresponding to said subject;
• (c) forming a distribution of the sequence lengths associated with each microsatellite locus in the said reference microsatellite loci dataset;
• and
• (d) determining a value based on said microsatellite loci-specific sequence length distribution, wherein a selected group of said microsatellite loci-specific values is indicative of a propensity for polymorphism.