Two Brothers, One Mutation, Different Fates
Two brothers inherit the same autosomal dominant mutation in a DNA mismatch-repair gene (MLH1). The older brother, now 55, developed colon cancer at 44 and had it resected. The younger brother, 52, has had three colonoscopies with no polyps. Their father died of colon cancer at 50; their paternal aunt died of endometrial cancer at 48. A cousin on their mother's side has no cancer history. Both brothers have normal complete blood counts and no other symptoms. The older brother asks why his brother is 'lucky' when they carry 'the same gene.'
1. Explain how two people with the same pathogenic variant can have different outcomes. Name at least three mechanisms, and state what the family history tells you about inheritance.
Read the worked answer
Same genotype does not guarantee same phenotype - this is incomplete penetrance and variable expressivity.
Mechanisms:
- Modifier genes - variants in other mismatch-repair or apoptosis genes alter risk.
- Second-hit / somatic events - cancer needs additional somatic mutations; timing and tissue differ between individuals.
- Environmental and lifestyle factors - diet, smoking, inflammation, screening history.
- Stochastic (chance) events - random mutation accumulation during stem-cell divisions.
- Epigenetic silencing - promoter methylation of the wild-type allele can differ.
The pedigree (father with colon cancer at 50, paternal aunt with endometrial cancer at 48) is consistent with an autosomal dominant cancer-predisposition syndrome (Lynch syndrome), with the mother's side unaffected. Each child of an affected parent has a 50% chance of inheriting the variant. The younger brother's clean colonoscopies do not prove he is unaffected - he carries the variant and remains at elevated risk.
2. The younger brother says: 'I've had three clear colonoscopies, so I can stop screening.' Evaluate this reasoning and propose an appropriate surveillance plan.
Read the worked answer
The reasoning is flawed. Clear screening reduces risk but does not remove it; Lynch syndrome carriers have markedly elevated lifetime colorectal and endometrial cancer risk, and cancers can arise in intervals between exams.
Appropriate plan (general principles):
- Continue colonoscopy at shortened intervals (typically every 1-2 years) starting young and continuing lifelong, regardless of prior negative results.
- Endometrial/ovarian surveillance discussion given the aunt's endometrial cancer - the family pattern includes extracolonic risk.
- Consider genetic counseling for relatives and risk-reducing options discussion.
- Report any new symptoms (bleeding, change in bowel habit, abnormal bleeding) promptly.
Key judgement: three negative tests change the probability, not the indication. Screening stops only per specialist guidance, not because of a run of negative results.