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Case history

Image not available. A 54-year-old man with a 3 week history of a change in bowel habit and abdominal pain was referred for urgent assessment. Investigations identified a 3.5 cm non-obstructing tumour in the ascending colon with no signs of significant lymphadenopathy or metastatic spread. Colonoscopy and biopsy demonstrated a moderately differentiated adenocarcinoma. His medical history included type 1 diabetes mellitus, complicated by mild sensory neuropathy. He was a teacher, married with two children and an ex-smoker of 20 years. His father was diagnosed with colorectal cancer at the age of 64.

The colorectal multidisciplinary team recommended primary resection of the tumour, and he proceeded to have a right hemicolectomy. Final pathological stage was pT3pN0 (0/21) M0V1R0 poorly differentiated adenocarcinoma of the ascending colon. Immunohistochemistry demonstrated a loss of expression of mutL protein homologue (MLH)-1 consistent with defective DNA mismatch repair (MMR). He was referred to the clinical genetics service and subsequently found to have a germline mutation in the MMR gene MLH1.

In view of the patient's pre-existing diabetic peripheral neuropathy he was considered unsuitable for standard adjuvant fluorouracil (5-FU), folinic acid and oxaliplatin (FOLFOX) chemotherapy. After considering his young age, poorly differentiated histology and DNA MMR status, however, his oncologist recommended 6 months of adjuvant 5-FU, folinic acid and irinotecan (FOLFIRI) combination chemotherapy. This was given, and he remains disease free at 5 years.

What is DNA MMR, and how does MMR deficiency lead to cancer?

What are the clinical features of inherited MMR gene mutation (Lynch syndrome [LS]), and how can we recognize and confirm this condition?

How does sporadic MMR deficiency occur in bowel cancer, and how does it differ from LS?

What is the impact of MMR deficiency, inherited or sporadic, on the prognosis and treatment choices for bowel cancer?

What primary and secondary cancer prevention strategies are advocated in individuals with LS?

What is DNA MMR, and how does MMR deficiency lead to cancer?

DNA MMR is a biological pathway that plays a key role in maintaining the stability of the genome. It is primarily concerned with the repair of base-base mismatches and small insertions or deletions acquired during DNA replication processes. Effective MMR therefore reduces the rate of spontaneous mutations. Mutations accumulate in cells with a deficiency of MMR activity, increasing the likelihood of carcinogenesis.

Replication errors most frequently occur in regions of microsatellite DNA (parts of the genome that have repetitive base sequences, normally 1–6 base pairs), as the replicative machinery more frequently 'slips' on repetitive sequences than on non-repetitive sequences.

Microsatellite instability (MSI) describes tumour cells with microsatellite regions that have changed in length, compared with the patient's normal tissue DNA, due to nucleotide insertions or deletions of the repeated motif. MSI is characteristic of an underlying MMR deficiency and can be identified using a panel of microsatellite markers targeted at mononucleotide repeats. They are classified as high, low or stable ...

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