Yong Alison Wang

Performance evaluation of predictive models for detecting MMR gene mutations associated with Lynch syndrome in cancer patients in a Chinese cohort in Taiwan

Abstract Identifying Lynch syndrome significantly impacts cancer risk management, treatment, and prognosis. Validation of mutation risk predictive models for mismatch repair (MMR) genes is crucial for guiding genetic counseling and testing, particularly in the understudied Asian population. We evaluated the performance of four MMR mutation risk predictive models in a Chinese cohort of 604 patients with colorectal cancer (CRC), endometrial cancer (EC), or ovarian cancer (OC) in Taiwan. All patients underwent germline genetic testing and 36 (6.0%) carried a mutation in the MMR genes ( MLH1 , MSH2 , MSH6 , and PMS2 ). All models demonstrated good performance, with area under the receiver operating characteristic curves comparable to Western cohorts: PREMM 5 0.80 (95% confidence interval [CI], 0.73–0.88), MMRPro 0.88 (95% CI, 0.82–0.94), MMRPredict 0.82 (95% CI, 0.74–0.90), and Myriad 0.76 (95% CI, 0.67–0.84). Notably, MMRPro exhibited exceptional performance across all subgroups regardless of family history (FH+ 0.88, FH‐ 0.83), cancer type (CRC 0.84, EC 0.85, OC 1.00), or sex (male 0.83, female 0.90). PREMM 5 and MMRPredict had good accuracy in the FH+ subgroup (0.85 and 0.82, respectively) and in CRC patients (0.76 and 0.82, respectively). Using the ratio of observed and predicted mutation rates, MMRPro and PREMM 5 had good overall fit, while MMRPredict and Myriad overestimated mutation rates. Risk threshold settings in different models led to different positive predictive values. We suggest a lower threshold (5%) for recommending genetic testing when using MMRPro, and a higher threshold (20%) when using PREMM 5 and MMRPredict. Our findings have important implications for personalized mutation risk assessment and counseling on genetic testing.

Attitude towards hereditary cancer risk management among women with cancer in Taiwan

Risk management intentions prior to genetic counseling predict risk management uptake following genetic testing. Limited studies examined the attitude and understanding towards genetic counseling/testing in underserved countries. The purposes of this study were to explore knowledge and attitude towards genetic counseling, testing, and risk management for breast and ovarian cancer, and to understand the factors influencing risk management intentions in women with cancer in Taiwan. Cross-sectional with correlational design was used in this study. Participants were enrolled for genetic testing based on clinical criteria suspected of having hereditary cancer. Survey was conducted using a standardized questionnaire including (1) demographics and personal/family history of cancer; (2) prior experience or consideration of genetic testing and reasons for not considering; (3) perception and attitude towards genetic counseling; and (4) intentions for risk management with a hypothetical BRCA1 mutation status. Multinomial logistic regression was used to analyze the predictors of participants' intentions for cancer risk management strategies. A total of 430 women with cancer were analyzed in which 51.6% had family history of cancer in first-degree relatives. Only 30.7% had considered genetic testing and 28.4% had known about genetic counseling prior to the study. When prompted with the services of genetic counseling, the attitude towards genetic counseling was fairly positive (score of 19.8 ± 2.9 out of 25). Given hypothetical BRCA1 mutation status, enhanced breast cancer screening with annual breast MRI was much more accepted than cancer risk reducing interventions. More positive attitude towards genetic counseling (each score point increase) was associated with higher odds of intention for breast MRI (OR 1.20, 95% CI 1.09-1.32) and preventive tamoxifen (OR 1.11, 95% CI 1.02-1.22). Having considered genetic testing prior to the study was associated with higher odds of intention for all four risk management strategies: breast MRI (OR 2.99, 95% CI 1.46-6.11), preventive tamoxifen (OR 1.79, 95% CI 1.00-3.17), risk-reducing mastectomy (OR 2.24, 95% CI 1.13-4.42), and risk-reducing salpingo-oophorectomy (OR 2.69, 95% CI 1.27-6.93). Knowledge of genetic testing and positive attitude towards genetic counseling were associated with increased willingness to consider cancer risk management strategies for hereditary breast and ovarian cancer syndrome. Given the limited knowledge on genetic testing and counseling in the studied population, increasing public awareness of these services may increase adoption of the risk management strategies.