Ramesar R S, Madden M V, Felix R, Harocopos C J, Westbrook C A, Jones G, Cruse J P, Goldberg P A
Department of Human Genetics, Groote Schuur Hospital.
S Afr Med J. 2000 Jul;90(7):709-14.
The syndrome of hereditary non-polyposis colorectal cancer (HNPCC) can be diagnosed fairly accurately using clinical criteria and a family history. Identifying HNPCC helps to prevent large-bowel cancer, or allows cancer to be treated at an early stage. Once the syndrome has been diagnosed a family member's risk can be judged approximately from a family tree, or it can now be predicted accurately if the causative mutation is known.
This study involved attempts to improve the management of a family with HNPCC over a period of 10 years. Clinical diagnostic criteria, colonoscopic surveillance, surgical treatment, genetic counselling, molecular genetic research, and finally predictive genetic testing were applied as they evolved during this time.
A rural general practitioner first noted inherited large-bowel cancer in the family and began screening subjects as they presented, using rigid sigmoidoscopy at the local hospital. At the time that the disorder was recognised as being HNPCC (1987), screening by means of colonoscopy at our university hospital was aimed primarily at first-degree relatives of affected individuals. After realising how many were at risk, screening was brought closer to the family. A team of clinicians and researchers visited the local hospital to identify and counsel those at risk and to perform screening colonoscopy. Family members were recruited for research to find the gene and its mutation that causes the disease, to develop an accurate predictive test and to reduce the number of subjects undergoing surveillance colonoscopies.
There are approximately 500 individuals in this family. In the 10 years of this study the number of subjects who have been counselled for increased genetic risk or who have requested colonoscopic surveillance for HNPCC in this kindred has increased from 20 to 140. After the causative mutation was found in the hMLH1 gene on chromosome 3, a test for it has reduced the number of subjects who need screening colonoscopy by over 70%. A protocol has been devised to inform family members, to acquire material for research in order to provide genetic counselling for (pre-test and post-test) risk, and to test for the mutation. Eventually, identifying those with the mutation should focus surveillance accurately.
The benefits of restricting screening to subjects with the mutation that causes colorectal cancer and of performing operations to prevent cancer are hard to measure accurately. However, it is likely that at least half the family members will be able to avoid colonoscopic screening, some deaths from cancer should be prevented, and the cost of preventing and treating cancer in the family should fall substantially.
遗传性非息肉病性结直肠癌（HNPCC）综合征可通过临床标准和家族病史进行较为准确的诊断。识别HNPCC有助于预防大肠癌，或使癌症能够在早期得到治疗。一旦诊断出该综合征，可通过家族树大致判断家庭成员的风险，若已知致病突变，现在则可准确预测。
本研究旨在尝试在10年时间里改善一个HNPCC家族的管理。在此期间，随着方法的不断发展，应用了临床诊断标准、结肠镜监测、手术治疗、遗传咨询、分子遗传学研究，最后进行了预测性基因检测。
一位乡村全科医生首先注意到该家族存在遗传性大肠癌，并在当地医院使用硬式乙状结肠镜对前来就诊的对象进行筛查。当该疾病被确认为HNPCC（1987年）时，我校医院通过结肠镜进行的筛查主要针对受影响个体的一级亲属。在意识到有多少人处于风险中后，筛查范围扩大到了更接近该家族的人群。一组临床医生和研究人员前往当地医院，识别并为有风险的人提供咨询，并进行结肠镜筛查。招募家庭成员参与研究，以寻找导致该疾病的基因及其突变，开发准确的预测性检测方法，并减少接受监测性结肠镜检查的人数。
这个家族大约有500人。在本研究的10年中，因遗传风险增加而接受咨询或要求进行HNPCC结肠镜监测的该家族成员数量从20人增加到了140人。在3号染色体上的hMLH1基因中发现致病突变后，针对该突变的检测使需要进行筛查性结肠镜检查的人数减少了超过70%。已经制定了一个方案，通知家庭成员，获取研究材料以便为（检测前和检测后）风险提供遗传咨询，并检测突变。最终，识别出有突变的人应能准确地聚焦监测。
将筛查限制在携带导致结直肠癌突变的对象身上以及进行预防癌症的手术所带来的益处难以准确衡量。然而，很可能至少一半的家庭成员将能够避免结肠镜筛查，一些癌症死亡应该能够得到预防，并且该家族预防和治疗癌症的成本应该会大幅下降。
