Managing Moderate Penetrance

Managing Moderate Penetrance Thomas Slavin, MD, FACMG Assistant Clinical Professor, Department of Medical Oncology, Division of Clinical Cancer Genetics Program Member, Cancer Control and Population Sciences City of Hope National Medical Center

Disclosures I do not have anything to disclose.

Objectives Describe the differences between a high, moderate, and low penetrance cancer susceptibility genes. Counsel a patient about moderate and low penetrance cancer susceptibility genes found on routine clinical i l testing Identify that moderate and low penetrance cancer susceptibility genes may not track with the family history of cancer. Recognize that cancer susceptibility genes on clinical panels are not always actionable.

Outline Background Moderate penetrance genes influence on breast, ovarian, and colorectal cancer. Incorporation into management and risk models Conclusions

Why are panels expanding? NGS, Patents, Pathways, candidate genes and emerging evidence (may add ~5 10%) http://www.rockefeller.edu/fanconi/mutate/

Results of MGP testing NBN 10% BRIP1 7% MRE11A 3% BARD1 RAD51D RAD50 2% 2% 2% CHEK2 29% ATM 14% MUTYH mono 14% PALB2 17% Select results from 348 commercial multigene panel tests ordered by Clinical Cancer Genetics Community of Practice clinicians between January 1, 2014, through October 1, 2014. Adapted from Slavin T.P. et al., Front. Oncol. 2015. 5:208.

Aren t more genes better? In theory Value In reality Genes

Distinguishing a moderate penetrance gene from a high or low penetrance gene Slavin TP, Niell-Swiller M, Solomon I, Nehoray B, Rybak C, Blazer KR and Weitzel JN (2015) Clinical application of multigene panels: challenges of next-generation counseling and cancer risk management. Front. Oncol. 2015. 5:208.

Cause of a given cancer High Penetrance gene Other factors

Cause of a given cancer Moderate Penetrance gene Other factors

Moderate penetrance genes influence on breast, ovarian, and colorectal cancer http://i2.wp.com/www.thesubtlelessons.com/wpcontent/uploads/2014/08/moving-target.gif

Breast cancer Gene Average relative risk Breast cancer ATM 2.8 (90% CI 2.2 3.7) CHEK2 (truncating) CHEK2 (missense) 3.0 (90% CI 2.6 3.5) 1.58 (95% CI 1.42 1.75) for I157T NBN 2.7 (90% CI 1.9 3.7) for c.657del5 PALB2 5.3 (90% CI 3.0 9.4) Adapted from Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8. Also see: Easton, D. F. et al. N. Engl. J. Med. 372, 2243 2257 (2015). Han, F. F., Guo, C. L. & Liu, L. H. DNA Cell Biol. 32, 329 335 (2013).

ATM Absolute Risk by 80 ~27% 2 High penetrance Australian variants (c.t7271g, IVS10 6T G; 2002 JNCI) High population prevalence No contraindication to radiation for therapy Bernstein JL and Women s environmental, cancer, and radiation epi study. Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study. JNCI J Natl Cancer Inst (2010) 102 (7): 475 483. Easton, D. F. et al. N. Engl. J. Med. 372, 2243 2257 (2015). Chenevix-Trench et al, Dominant Negative ATM Mutations in Breast Cancer Families. JNCI J Natl Cancer Inst (2002) 94 (3): 205-215. Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8.

CHEK2 CHEK2 (truncating) CHEK2 (missense) Absolute risk ~29% Absolute risk ~18% for I157T Easton, D. F. et al. N. Engl. J. Med. 372, 2243 2257 (2015). Han, F. F., Guo, C. L. & Liu, L. H. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 32, 329 335 (2013).

NBN RR: 2.7 (90% CI 1.9 3.7) for c.657del5 (ONLY!) Absolute risk ~23% Zhang G, Zeng Y, Liu Z, Wei W. Significant association between Nijmegen breakage syndrome 1 657del5 polymorphism and breast cancer risk. Tumour Biol 2013; 34: 2753-7.

Antoniou AC et al. N Engl J Med 2014;371:497 506. PALB2

Risk of Breast Cancer for Female PALB2 Mutation Carriers, According to Family History of Breast Cancer. Antoniou AC et al. N Engl J Med 2014;371:497 506.

Contralateral breast

No strong breast cancer association at BARD1 BRIP1 RAD50 RAD51C RAD51D XRCC2 SLX4 this time (2016) Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8. http://www.greenbookblog.org/wp-content/uploads/2015/05/finish.png

Ovarian Cancer Ovarian cancer BRIP1 RAD51C/RAD51D 11.2 (95% CI 3.22 34.10) in case control 3.41 (95% CI 2.12 5.54) in segregation analysis 5.2 (95% C.I. 1.1 24) for RAD51C 12 (95% C.I. 1.5 90) for RAD51D Ramus, S. J. et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J. Natl Cancer Inst. 107, djv214 (2015). Song, H. et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J. Clin. Oncol. 33, 2901 2907 (2015). Tung et al. 2016. Counselling framework for moderate penetrance cancer susceptibility mutations. Nature reviews. Vol 13: 581 8.

Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8.

PALB2? Among 154 families, relative risk of ovarian cancer among PALB2 mutation carriers was 231(95% 2.31 CI, 0.77 077to 6.97;P = 0.18) 018) Significant in a large case controlled analysis with OR of 10.9 (95% CI 4.6 26.0) 4626 Antoniou A.C., et al. Breast Cancer Risk in Families with Mutations in PALB2. N Engl J Med 2014;371:497 506. Norquist BM, Harrell MI, Brady MF, et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016;2(4):482 490.

No strong ovarian cancer association ATM BARD1 CHEK2 MRE11A NBN RAD50 RAD51B XRCC2 SLX4 at this time (2016) Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8. http://image.tutorvista.com/content/feed/u834/untitled_57.jpg

Colorectal Cancer Colorectal cancer APC I1307K 2.17 (95% C.I. 1.64 2.86) 1.88 (95% C.I. 1.29 2.73) for 1100delC CHEK2 156(95% 1.56 C.I. CI 1.32 132 1.84) for I157T MUTYH (monoallelic) 1.17 (95% C.I. 1.01 1.34) Level associated an affected first-degree relative with CRC (RR 2.25, 95% CI 2.00 2.53); APC I1307K and CHEK2 1100delC overlap this range. Liang, J. et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta analysis. Am. J. Epidemiol. 177, 1169 1179 (2013). Ma, X., Zhang, B. & Zheng, W. Genetic et variants a tsassociated ated with colorectal o cancer ce risk: comprehensive e eresearch synopsis, s, meta analysis, and epidemiological evidence. Gut 63, 326 336 (2014). Johns, L. E. & Houlston, R. S. A systematic review and meta analysis of familial colorectal cancer risk. Am. J. Gastroenterol. 96, 2992 3003 (2001). Tung et al. 2016. Counselling framework for moderate penetrance cancer susceptibility mutations. Nature reviews. Vol 13: 581 8.

Mutation classifications do not indicate penetrance Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of MedicalGenetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405 24. Freely available online. IARC Unclassified Genetic Variants Working Group, HUMAN MUTATION 29(11),1282-1291, 2008 (1) Pathogenic (2) Likely pathogenic (3) Uncertain significance (4) Likely benign (5) Benign

Moderate risk CRC gene management

Other rare (unclear risk, presumed high h from reported dfamilies) Polymerase proofreading associatedassociated polyposis POLD1 and POLE <50 polyps Early onset CRC and/or adenomas GREM1 Mixed polyposis syndrome due to a 40kb duplication upstream of GREM1 (AJ ancestry) Management: Colonoscopy at 25, q 2 3yrs if negative, 1 2 yrs if polyps (NCCN). Palles C et al. Nat. Genet. 2013Feb;45(2):136-44 NCCN Genetic/Familial HR Assiessment:CRC 2016, Version 1 Valle L et al. Hum. Mol. Genet. 2014 Jul;23(13):3506-12 Jaeger E, et al. Nat Genet 2012; 44:699-703

So BARD1 FANCC MRE11A RAD50 XRCC2 SLX4 RAD51B other NBN https://captnsblog.files.wordpress.com/2010/08/strike-out.jpg

Even healthy populations have mutations http://www.mycariboonow.com/wp-content/uploads/2016/02/population.jpg

Managing the Moderate

BOADICEA Testing negative for a known familial moderate risk gene mutation does not completely reduce risk to the general population. Lee A.J., et al., Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. Genet Med. 2016 Apr 14

Guidelines change! (2015) NCCN Guidelines Version 1 (2015), Genetic/Familial High-Risk Assessment: Breast and Ovarian

Guidelines change! (2016) 2017: PALB2, ages? Recommend carriers check back or set up follow ups NCCN Guidelines Version 1 (2016), Genetic/Familial High-Risk Assessment: Breast and Ovarian

APC I1307K? Tung et al. 2016. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nature reviews. Vol 13: 581-8. APC I1307K added.

Prenatal/ preimplantation genetics ATM Ataxia telangiectasia telangiectasia BLM Bloom syndrome NBN Nijmegen breakage syndrome Fanconi Anemia pathway genes http://www.rockefeller.edu/fanconi/mutate/

CHEK2, c.1100delc

ATM, c.3802delg

Next steps of moderate penetrance: PRS Mavaddatt N. et al, Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015 Apr 8;107(5)

Summary Moderate penetrance genes should ldbe treated differently than high penetrance genes They may not track with the family history of cancer More research is being done to better define the absolute risk for and spectrum of associated cancers Specific geno pheno correlations (i.e., NBN) Screening recommendations may differ

Questions?