Discrepancy between initial high expression of interest in clinical cancer genetic testing and actual low uptake in an Asian population.

AIMS: Little is known about the acceptance of clinical cancer genetic testing in Asians. We surveyed the attitudes and perceived motivators and barriers to genetic testing immediately after genetic counseling in at-risk patients for hereditary cancer in a cancer genetics clinic in Singapore, and compared the responses of actual test acceptors and decliners. RESULTS: Three hundred seventeen patients participated, including 199 cancer-affected and 118 cancer-free probands or family members. Overall, 70% of patients expressed an initial willingness to be tested, and most did not perceive major barriers. However, only 69/199 (35%) of cancer-affected probands were actually tested. There was no significant difference in age, education, marital status, or initial expression of negative feelings toward genetic information between the test acceptors and decliners, although the decliners were more likely to have indicated a wish not to be tested (22% vs. 4%, p<0.001) and cited cost as a barrier (32% vs. 12%, p=0.002). The most common actual reasons against testing were cost (60%), not wanting to bear the emotional burden of genetic information (16%), and the perception that the medical management will not change (16%). CONCLUSION: A significant discrepancy exists between an initial high interest in testing and actual low uptake. Health programs that address cost issues and education to correct misperceptions may improve genetic information utilization.

Non-directive genetic counselling - respect for autonomy or unprofessional practice?

Historically, genetic counselling was developed in the West and in the field of neonatal medicine, and a non-directive approach has been its central ethos since the 1950s to 60s. In today's changing world, the question of whether non-directive genetic counselling with its emphasis on patient autonomy may in some occasions be perceived as unprofessional practice. Through these 4 case studies in cancer genetic counselling, we seek to highlight the conundrums, dilemmas and various other considerations of patients and their families faced during the genetic counselling process. We also address the pitfalls of a 'one-size fi ts all' approach of non-directive counselling and how we could best practice cancer genetic counselling in the Singapore context, taking into consideration respect for patient autonomy and healthcare professionalism.

Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore.

Lynch syndrome is an autosomal dominant disorder due to mutations in DNA mismatch repair genes, causing young onset colorectal cancer and extra-colonic cancers such as endometrial and stomach cancers. We genotyped MLH1 and MSH2 in patients suspected to have Lynch syndrome and correlated patient clinical characteristics and family history with deleterious mutations. Eighty-five unrelated patients participated. Comprehensive sequencing was performed for MLH1 and MSH2, including all coding regions, splice-site junctions and promoter regions. Of the 29 different mutations found, 11 were deleterious, of which 10 were in MLH1 and 1 in MSH2. Three recurring MLH1 deleterious mutations were found in two unrelated Chinese patients each, and haplotype analysis suggested common ancestral origin for the recurring mutations and possible founder effect. Families with clinical diagnosis of HNPCC (i.e. family history which fulfills the Amsterdam I/II criteria) was the strongest predictor for finding a deleterious mutation, and stomach cancer was the most commonly reported extra-colonic cancer in families found with a deleterious MLH1 or MSH2 mutation. The observation of recurring deleterious MLH1 mutations in our study suggests possible founder effect and may have implications on genetic testing in Asia.

Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3.

The purpose was to validate the use of RUNX3 as a potential biomarker for detection of cancer in serum samples and to determine its sensitivity alone and in combination with p16, RASSF1A and CDH1 using methylation-specific polymerase chain reaction (MSP). We examined the promoter methylation status of RUNX3, p16, RASSF1A and CDH1 by MSP using the serum of 70 metastatic breast, non-small cell lung, gastric, pancreatic, colorectal or hepatocellular carcinomas. The DNA from 10 healthy serum controls was used to determine the specificity of methylation. According to our results, promoter hyper-methylation of RUNX3 was detected in the serum of 44 patients comprising breast 9/19 (47%), non-small cell lung 11/20 (55%), gastric 4/4 (100%), pancreatic 2/2 (100%), colorectal 11/17 (65%) and liver 7/8 (88%) carcinomas. Comparative figures for the other genes were as follows: p16 - 39/70 (7/19, 10/20, 2/4, 0/2, 12/17, 8/8); RASSF1A - 24/70 (8/19, 6/20, 1/4, 1/2, 4/17, 4/8); CDH1 - 10/70 (0/19, 4/20, 1/4, 1/2, 3/17, 1/8). Using a panel of four genes, hypermethylation of one or more genes was found in 62/70 samples (15/19, 19/20, 4/4, 2/2, 14/17, 8/8). A panel of three genes omitting RUNX3 detected hyper-methylation in only 50/70 samples. No methylation was detected in the 10 healthy serum controls. Thus, RUNX3 can be detected in the serum of a high proportion of advanced cancers. This suggests that serum hypermethylation of RUNX3 is at least as, or possibly more sensitive a marker, than other tumor suppressor genes currently under investigation. Inclusion of RUNX3 in gene panels can potentially increase the sensitivity of such panels for serum diagnosis of malignancies and warrants further study.

Establishing a cancer genetics programme in Asia - the singapore experience.

Cancer genetics is now an established oncology subspecialty with the primary prevention role of identifying high-risk individuals through genetic information for enrolment into screening and preventive programmes. Integrated into major Western centres since the late 1990s, such a programme has been established in Singapore since 2001. Our programme has evaluated 367 index patients comprising mainly breast and colorectal cancer cases. Cancer patients were receptive to genetic counselling, but cost posed a major barrier to genetic testing. However, when the cost barrier was removed through government subsidy plans, more than half of high-risk patients still declined testing. The major barriers were reluctance to involve family members, perception that the information would not change management, and fears of negative feelings. Confirmed mutation carriers were compliant to screening and receptive to prophylactic surgery. Uptake of predictive testing among cancer-free family members has been low, possibly arising from the stigma associated with cancer in our Asian culture. These potential barriers are being addressed through government subsidy plans, continuing education to increase awareness, and being culturally sensitive when dealing with the Asian family.