Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants

Abstract

Background

Carriers of pathogenic variants (PVs) in moderate–high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear.

Methods

Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018.

Results

Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals.

Conclusions

The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

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References

  1. 1.

    Foulkes WD (2008) Inherited susceptibility to common cancers. N Engl J Med 359:2143–2153

    CAS  Article  Google Scholar 

  2. 2.

    Easton DF, Pharoah PDP, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL et al (2015) Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243–2257

    CAS  Article  Google Scholar 

  3. 3.

    Whitworth J, Skytte A-B, Sunde L, Lim DH, Arends MJ, Happerfield L et al (2016) Multilocus inherited neoplasia alleles syndrome: a case series and review. JAMA Oncol 2:373–379

    Article  Google Scholar 

  4. 4.

    Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME (2013) Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 31:1267–1270

    Article  Google Scholar 

  5. 5.

    Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL (2015) A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17:70–87

    Article  Google Scholar 

  6. 6.

    Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A et al (2017) Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA 318:825–835

    Article  Google Scholar 

  7. 7.

    Bernstein-Molho R, Laitman Y, Schayek H, Reish O, Lotan S, Haim S et al (2018) The yield of targeted genotyping for the recurring mutations in BRCA1/2 in Israel. Breast Cancer Res Treat 167:697–702

    CAS  Article  Google Scholar 

  8. 8.

    Liang J, Lin C, Hu F, Wang F, Zhu L, Yao X et al (2013) APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol 177:1169–1179

    Article  Google Scholar 

  9. 9.

    Gilad S, Bar-Shira A, Harnik R, Shkedy D, Ziv Y, Khosravi R et al (1996) Ataxia-Telangiectasia: founder effect among North African Jews. Hum Mol Genet 5:2033–2037

    CAS  Article  Google Scholar 

  10. 10.

    Shaag A, Walsh T, Renbaum P, Kirchhoff T, Nafa K, Shiovitz S et al (2005) Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555–563

    CAS  Article  Google Scholar 

  11. 11.

    Han F, Guo C, Liu L (2013) The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol 32:329–335

    CAS  Article  Google Scholar 

  12. 12.

    Yakobson E, Eisenberg S, Isacson R, Halle D, Levy-Lahad E, Catane R et al (2003) A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families. Eur J Hum Genet 11:288–296

    CAS  Article  Google Scholar 

  13. 13.

    Zick A, Kadouri L, Cohen S, Frohlinger M, Hamburger T, Zvi N et al (2017) Recurrent TP53 missense mutation in cancer patients of Arab descent. Fam Cancer 16:295–301

    CAS  Article  Google Scholar 

  14. 14.

    Raskin L, Schwenter F, Freytsis M, Tischkowitz M, Wong N, Chong G et al (2011) Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin Genet 79:512–522

    CAS  Article  Google Scholar 

  15. 15.

    Mukherjee B, Rennert G, Ahn J, Dishon S, Lejbkowicz F, Rennert HS et al (2011) High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. Gastroenterology 140:1919–1926

    Article  Google Scholar 

  16. 16.

    Lejbkowicz F, Cohen I, Barnett-Griness O, Pinchev M, Poynter J, Gruber SB et al (2012) Common MUTYH mutations and colorectal cancer risk in multiethnic populations. Fam Cancer 11:329–335

    CAS  Article  Google Scholar 

  17. 17.

    Locker GY, Lynch HT (2004) Genetic factors and colorectal cancer in Ashkenazi Jews. Fam Cancer 3:215–221

    Article  Google Scholar 

  18. 18.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med Off J Am Coll Med Genet 17:405–424

    Google Scholar 

  19. 19.

    Woodage T, King SM, Wacholder S, Hartge P, Struewing JP, McAdams M et al (1998) The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nat Genet 20:62–65

    CAS  Article  Google Scholar 

  20. 20.

    Niell BL, Long JC, Rennert G, Gruber SB (2003) Genetic anthropology of the colorectal cancer–susceptibility allele APC I1307K: evidence of genetic drift within the Ashkenazim. Am J Hum Genet 73:1250–1260

    CAS  Article  Google Scholar 

  21. 21.

    Fidder H, Figer A, Geva R, Flex D, Schayek H, Avidan B et al (2005) Genetic analyses in consecutive Israeli Jewish colorectal cancer patients. Am J Gastroenterol 100:1376–1380

    CAS  Article  Google Scholar 

  22. 22.

    Leshno A, Shapira S, Liberman E, Kraus S, Sror M, Harlap-Gat A et al (2016) The APC I1307K allele conveys a significant increased risk for cancer. Int J Cancer 138:1361–1367

    CAS  Article  Google Scholar 

  23. 23.

    Walsh T, Mandell JB, Norquist BM, Casadei S, Gulsuner S, Lee MK et al (2017) Genetic predisposition to breast cancer due to mutations other than BRCA1 and BRCA2 founder alleles among Ashkenazi Jewish women. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2017.1996

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE et al (2016) Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol 13:581–588

    CAS  Article  Google Scholar 

  25. 25.

    Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S et al (2017) NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Canc Netw. 15:9–20

    CAS  Article  Google Scholar 

  26. 26.

    Ma X, Zhang B, Zheng W (2014) Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut 63:326–336

    CAS  Article  Google Scholar 

  27. 27.

    Liu C, Wang QS, Wang YJ (2012) The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 13(5):2051–2055

    Article  Google Scholar 

  28. 28.

    de Jong MM, Nolte IM, te Meerman GJ, van der Graaf WTA, Mulder MJ, van der Steege G et al (1100delC) Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 43:377–382

    Article  Google Scholar 

  29. 29.

    Laitman Y, Boker-Keinan L, Berkenstadt M, Liphsitz I, Weissglas-Volkov D, Ries-Levavi L et al (2016) The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers. Cancer Genet 209:70–74

    CAS  Article  Google Scholar 

  30. 30.

    Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K et al (2015) Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 121:25–33

    CAS  Article  Google Scholar 

  31. 31.

    Roberts ME, Jackson SA, Susswein LR, Zeinomar N, Ma X, Marshall ML et al (2018) MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med. https://doi.org/10.1038/gim.2017.254

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Espenschied CR, LaDuca H, Li S, McFarland R, Gau C-L, Hampel H (2017) Multigene panel testing provides a new perspective on Lynch Syndrome. J Clin Oncol 35:2568–2575

    CAS  Article  Google Scholar 

  33. 33.

    Bernstein-Molho R, Laitman Y, Schayek H, Iomdin S, Friedman E (2019) The rate of the recurrent MSH6 mutations in Ashkenazi Jewish breast cancer patients. Cancer Causes Control 30:97–101

    Article  Google Scholar 

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Acknowledgements

The authors wish to acknowledge Sofia Naftaly Nathan BSc, Study Coordinator and Levona Lago Krispin from Fugene Genetics for data managing.

Funding

The work had no specific funding.

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Correspondence to Yael Goldberg.

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All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Bernstein-Molho, R., Friedman, E., Kedar, I. et al. Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants. Breast Cancer Res Treat 181, 445–453 (2020). https://doi.org/10.1007/s10549-020-05633-2

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Keywords

  • Multi-gene panel testing
  • Low-penetrance variants
  • Recurrent mutations
  • Clinical utility
  • Cancer predisposition
  • Inherited cancer syndromes