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18.04.2020 | Epidemiology

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

verfasst von: Rinat Bernstein-Molho, Eitan Friedman, Inbal Kedar, Yael Laitman, Tanir M. Allweis, Einav Nili Gal-Yam, Hagit Baris Feldman, Albert Grinshpun, Naama Halpern, Shulamit Hartmajer, Luna Kadouri, Lior H. Katz, Bella Kaufman, Ido Laish, Keren Levanon, Shira Litz Philipsborn, Mark Ludman, Gal Moran, Tamar Peretz, Eyal Reinstein, Gili Reznick Levi, Tamar Safra, Shiri Shkedi, Chana Vinkler, Zohar Levy, Yael Goldberg

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2020

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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.

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

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 372:2243–2257CrossRef

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 2:373–379CrossRef

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 31:1267–1270CrossRef

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 17:70–87CrossRef

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 318:825–835CrossRef

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 167:697–702CrossRef

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 177:1169–1179CrossRef

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 5:2033–2037CrossRef

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 14:555–563CrossRef

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 32:329–335CrossRef

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 11:288–296CrossRef

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 16:295–301CrossRef

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 79:512–522CrossRef

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 140:1919–1926CrossRef

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 11:329–335CrossRef

17.

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

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

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 20:62–65CrossRef

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 73:1250–1260CrossRef

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 100:1376–1380CrossRef

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 138:1361–1367CrossRef

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 CrossRefPubMedPubMedCentral

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 13:581–588CrossRef

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. 15:9–20CrossRef

26.

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

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):2051–2055CrossRef

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 43:377–382CrossRef

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 209:70–74CrossRef

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 121:25–33CrossRef

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 CrossRefPubMedPubMedCentral

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 35:2568–2575CrossRef

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 30:97–101CrossRef

Titel: Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants
verfasst von: Rinat Bernstein-Molho
Eitan Friedman
Inbal Kedar
Yael Laitman
Tanir M. Allweis
Einav Nili Gal-Yam
Hagit Baris Feldman
Albert Grinshpun
Naama Halpern
Shulamit Hartmajer
Luna Kadouri
Lior H. Katz
Bella Kaufman
Ido Laish
Keren Levanon
Shira Litz Philipsborn
Mark Ludman
Gal Moran
Tamar Peretz
Eyal Reinstein
Gili Reznick Levi
Tamar Safra
Shiri Shkedi
Chana Vinkler
Zohar Levy
Yael Goldberg
Publikationsdatum: 18.04.2020
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2020
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-020-05633-2

Springer Medizin

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