A 34-year-old woman comes to the physician with abdominal pain and melena. She also complains of progressive fatigue and a 5 kg (11 lb) weight loss over the last 2 months. She has a strong family history of colon, endometrial, and ovarian cancer. Colonoscopy shows a protuberant, friable mass in the ascending colon, and biopsy is diagnostic for colon adenocarcinoma. Genetic analysis confirms a mutation consistent with Lynch syndrome (hereditary nonpolyposis colon cancer). Which of the following is most likely responsible for the development of colon cancer in this patient?

Question

A 34-year-old woman comes to the physician with abdominal pain and melena.  She also complains of progressive fatigue and a 5 kg (11 lb) weight loss over the last 2 months.  She has a strong family history of colon, endometrial, and ovarian cancer.  Colonoscopy shows a protuberant, friable mass in the ascending colon, and biopsy is diagnostic for colon adenocarcinoma.  Genetic analysis confirms a mutation consistent with Lynch syndrome (hereditary nonpolyposis colon cancer).  Which of the following is most likely responsible for the development of colon cancer in this patient?

Quizplus · Accepted Answer

Lynch syndrome (hereditary nonpolyposis colon cancer) is an autosomal dominant disease caused by defective DNA mismatch repair. DNA replication occurs with a high degree of fidelity because mismatched nucleotides are repaired through the proofreading activity of DNA polymerases delta and epsilon. However, this proofreading functionality is not infallible; base substitutions and small insertion-deletion mismatches occur due to errors in base pairing every 10⁶ bases on average. It is the function of the DNA mismatch repair system to fix these errors shortly after the daughter strands are synthesized. The mismatch repair system involves several genes, including MSH2 and MLH1, which code for components of the human MutS and MutL homologs. Mutations in these 2 genes account for around 90% of cases of Lynch syndrome. Mismatch repair begins with MutS homolog detecting a mismatch on the newly created daughter strand, which is distinguished from the parent strand by occasional nicks in the phosphodiester bonds. MutL homolog is then recruited, and the resulting complex slides along the DNA molecule until 1 of the daughter strand nicks is encountered. At this point, exonuclease 1 is loaded onto and activated by the repair complex. The daughter strand is then degraded backward past the initial mismatch point, leaving a variable gap of single-stranded DNA that is stabilized by ssDNA-binding protein. The complex then dissociates while DNA polymerase delta loads at the 3' end of the discontinuity and begins synthesizing a new daughter strand segment. Finally, DNA ligase I seals the remaining nick to complete the repair process. (Choice B) Exposure to ultraviolet light can cause pyrimidine (usually thymine) dimers to form due to covalent joining of adjacent pyrimidines. Pyrimidine dimers interfere with DNA replication and are removed by nucleotide excision repair. (Choices C and D) Several types of insults can alter the DNA bases. For example, nitrous acid can deaminate C, A, and G. There are also spontaneous changes, such as deamination of C to U and the constant low-level loss of purines via thermal disruption. Glycosylases are enzymes that detect and remove abnormal bases from DNA, creating an empty sugar-phosphate residue that is subsequently removed and replaced by the correct nucleotide (base excision repair). (Choice E) Exposure to ionizing radiation causes double-stranded DNA breaks that are repaired by end-joining repair mechanisms. Non-homologous end joining, the main mechanism in primates, is more prone to cause mutations than homologous recombination. Educational objective: Lynch syndrome is an autosomal dominant disease caused by abnormal nucleotide mismatch repair. The mismatch repair system involves several genes, including MSH2 and MLH1, which code for components of the human MutS and MutL homologs. Mutations in these 2 genes account for around 90% of cases of Lynch syndrome.

A 34-Year-Old Woman Comes to the Physician with Abdominal Pain