DNA Modifications/Mutations and Gene Sequencing

Written By Yuriko Beaman

Two genetic disorders that increase an individual's risk of developing cancer significantly above the general population are Lynch syndrome and Xeroderma Pigmentosum. Lynch syndrome is associated with an increased risk of colon cancer, among others. Xeroderma Pigmentosum is associated with an increased risk of developing skin cancer. These genetic disorders/syndromes are caused by errors in single-stranded DNA damage repair mechanisms. Mismatched repair errors cause Lynch syndrome and nucleotide excision repair errors cause Xeroderma Pigmentosum. Lynch syndrome is autosomal dominant and more common, and Xeroderma Pigmentosum is autosomal recessive and a rare disorder. This syndrome is a "cancer predisposition syndrome" typically caused by a DNA repair error (Nussbaum et al., 2015). Individuals with LS have a mutation in their mismatched DNA repair gene.

For patients:

DNA relies upon specifically matched pairs to form its double helix structure and create specific proteins. For example, the nucleotide adenine (A) is paired with thymine (T), and the nucleotides cytosine (C) and guanine (G) are also paired together. The sequence of these nucleotides determines the genetic code. Therefore, if pairs are incorrectly matched, T with G, the pairing is a mismatch.

The known mismatch repair genes are "MLH1, MSH2, MSH6, and PMS2" (Nussbaum et al., 2015). When mismatch repair occurs, the DNA's incorrect pairing of the nucleotides is not fixed. Fortunately, there are two copies of each gene. The gene loses function when both copies are mutated, and the repair gene error causes cancer. Per Nussbaum et al., the following cancers are associated with lynch syndrome: “cancer of the stomach, small bowel, pancreas, kidney, endometrium, and ovaries.” Some of the risks associated with Lynch syndrome include (Nussbaum et al., 2015):

  • “90% lifetime risk for development of colon cancer and one of these associated cancers, or both” (see above for associated cancers)

  • “50% risk for having a child carrying a germline mutation”

  • “Each child carrying such a mutation has a lifetime cancer risk of up to 90%”

Prenatal diagnosis for Lynch Syndrome is not widely practiced. However, genetic Counselors can look for the following to document the need for genetic testing for lynch syndrome (Nussbaum et al., 2015):

  • “occurrence of colorectal cancer or another Lynch syndrome-associated tumor in three members of a family, at least two of whom are first-degree relatives,”

  • Occurrence “across two or more generations”

  • “development of colorectal cancer in at least one affected individual before the age of 50 years”

Xeroderma Pigmentosum (XP) is a rare disorder, but like Lynch syndrome, it is associated with an increased risk for cancer. In addition, XP is associated with the following (GeneReviews, 2022):

  • “Acute sun sensitivity”

  • “Sunlight-induced ocular involvement, such as atrophy of the skin of the lids”

  • “Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life.”

In addition, less than 20% of individuals experience "progressive neuronal degeneration." The severity of nucleotide excision repair errors determines the severity of these neurological symptoms. Progressive neuronal degeneration is characterized by: "sensorineural deafness, mental retardation, spasticity, hyporeflexia or areflexia, segmental demyelination, ataxia, choreoathetosis, and supra-nuclear ophthalmoplegia," (Nussbaum et al., 2015).

Longevity is diminished, and individuals with XP's lifespan is 30 years shorter than the general population. XP is an autosomal recessive disorder. Therefore, familial history of the disorder is rare. However, if one child has XP, the risk of other children with XP from the same parents is 25%. "Prenatal diagnosis is possible by functional testing of DNA repair and UV sensitivity in cultured amniocytes or chorionic villi or molecular testing if the mutations have been identified" (GeneReviews). There are many genes involved in XP, and it is nucleotide excision repair errors. However, 27 - 30% are associated with XPC and XPA genes, respectively (GeneReviews).

DNA mismatch repair corrects errors that occur during DNA replication. When nucleotides are not paired together correctly and this mechanism is activated. Exonucleases or enzymes are designed to cut the DNA, cut out the error, and remove the mismatched base. The other repair mechanism discussed, nucleotide excision repair, is needed to remove the formation of dimers or groups) and chemically modified nucleotides ( Hardison, 2021). The image below depicts NER and is copied  from Essentials of Genetics, 2021.

For Physicians:

Nuclease, an enzyme, excises or cuts out the damaged DNA. The gap in DNA is filled by DNA polymerase I and DNA ligase seal the gap filled by DNA polymerase I.

References:

Hardison, R. C. (2021, July 19). 7.4: Repair mechanisms. Biology LibreTexts. Retrieved September 15, 2022, from https://bio.libretexts.org/ Bookshelves/Genetics/ Book%3A_Working_with_Molecular_Genetics_(Hardison)/Unit_II%3A_Replication_Maintenance_and_Alteration_of_the_Genetic_Material/ 7%3A_Mutation_and_Repair_of_DNA/7.4%3A_Repair_Mechanisms

Klug, W. S., Cummings, M. R., Spencer, C. A., Palladino, M. A., & Killian, D. J. (2021). Essentials of genetics. Harlow, Essex, United Kingdom: Pearson.

Kraemer KH, DiGiovanna JJ, Tamura D. Xeroderma Pigmentosum. 2003 Jun 20 [Updated 2022 Mar 24]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1397/

Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2015). Thompson & Thompson Genetics in medicine. Elsevier.

Yuriko Beaman
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