Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative

Jennifer L Caswell-Jin, Anjali D Zimmer, Will Stedden, Kerry E Kingham, Alicia Y Zhou, Allison W Kurian, Jennifer L Caswell-Jin, Anjali D Zimmer, Will Stedden, Kerry E Kingham, Alicia Y Zhou, Allison W Kurian

Abstract

In cascade testing, genetic testing for an identified familial pathogenic variant extends to disease-free relatives to allow genetically targeted disease prevention. We evaluated the results of an online initiative in which carriers of 1 of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. In the first year, 1101 applicants invited 2280 first-degree relatives to undergo genetic testing. Of invited relatives, 47.5% (95% confidence interval [CI] = 45.5 to 49.6%) underwent genetic testing, and 12.0% (95% CI = 9.2 to 14.8%) who tested positive continued the cascade by inviting additional relatives to test. Of tested relatives, 4.9% (95% CI = 3.8 to 6.1%) had a pathogenic variant in a different gene from the known familial one, and 16.8% (95% CI = 14.7 to 18.8%) had a variant of uncertain significance. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that up to 5% of the general population may carry a pathogenic variant in 1 of 30 cancer-associated genes.

Figures

Figure 1.
Figure 1.
The family testing program. A) Flowchart of the application process. Positive results were available only after telephone-based genetic counseling, and posttest genetic counseling was also optionally available if the results were variant of uncertain significance or negative. B) Affected genes and uptake of testing. FDR = first-degree relative.
Figure 2.
Figure 2.
Panel testing results of first-degree relatives of carriers. A) Overall results. B) Unexpected pathogenic variants.

References

    1. Daly MB, Pilarski R, Berry M, et al. NCCN guidelines insights: Genetic/familial high-risk assessment: breast and ovarian, Version 2.2017. J Natl Compr Canc Netw. 2017;151:9–20.
    1. Samimi G, Bernardini MQ, Brody LC, et al. Traceback: A proposed framework to increase identification and genetic counseling of BRCA1 and BRCA2 mutation carriers through family-based outreach. J Clin Oncol. 2017;3520:2329–2337.
    1. Louter L, Defesche J, Roeters van Lennep J.. Cascade screening for familial hypercholesterolemia: Practical consequences. Atheroscler Suppl. 2017;30:77–85.
    1. Knowles JW, Rader DJ, Khoury MJ.. Cascade screening for familial hypercholesterolemia and the use of genetic testing. JAMA. 2017;3184:381–382.
    1. George R, Kovak K, Cox SL.. Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases. J Genet Counsel. 2015;243:388–399.
    1. Whitworth P, Beitsch P, Arnell C, et al. Impact of payer constraints on access to genetic testing. J Oncol Pract. 2017;131:e47–e56.
    1. Katz SJ, Kurian AW, Morrow M.. Treatment decision making and genetic testing for breast cancer: Mainstreaming mutations. JAMA. 2015;31410:997–998.
    1. Offit K, Bradbury A, Storm C, et al. Gene patents and personalized cancer care: Impact of the Myriad case on clinical oncology. J Clin Oncol. 2013;3121:2743–2748.
    1. Stadler ZK, Schrader KA, Vijai J, et al. Cancer genomics and inherited risk. J Clin Oncol. 2014;327:687–698.
    1. Bradbury AR, Patrick-Miller LJ, Egleston BL, et al. Randomized noninferiority trial of telephone vs in-person disclosure of germline cancer genetic test results. J Natl Cancer Inst. 2018;1109:985–993.
    1. Kinney AY, Steffen LE, Brumbach BH, et al. Randomized noninferiority trial of telephone delivery of BRCA1/2 genetic counseling compared with in-person counseling: 1-year follow-Up. J Clin Oncol. 2016;3424:2914–2924.
    1. Sermijn E, Delesie L, Deschepper E, et al. The impact of an interventional counselling procedure in families with a BRCA1/2 gene mutation: Efficacy and safety. Fam Cancer. 2016;152:155–162.
    1. Ricker CN, Koff RB, Qu C, et al. Patient communication of cancer genetic test results in a diverse population. Transl Behav Med. 2018;81:85–94.
    1. Forrest LE, Burke J, Bacic S, et al. Increased genetic counseling support improves communication of genetic information in families. Genet Med. 2008;103:167–172.
    1. Sharaf RN, Myer P, Stave CD, et al. Uptake of genetic testing by relatives of lynch syndrome probands: A systematic review. Clin Gastroenterol Hepatol. 2013;119:1093–1100.
    1. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;24:482–490.
    1. Tung N, Lin NU, Kidd J, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol. 2016;3413:1460–1468.
    1. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;334:304–311.
    1. Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;3510:1086–1095.

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