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Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment

Volume 32, Number 19, July. 1, 2014, from J Clin OncolChen XinyiOctober 29,20151

BACKGROUND The BRCAs account for only about 25% of breast cancers with a hereditary component; Now unmasked dozens of other genes associated with breast cancer; Whether and how?

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INTRODUCTION

Sam Kean Science 2014.03 3

QUESTIONHow many and which genes to sequence?Whether results are sufficiently understood to guide intervention?How best to counsel patients about variants of low or moderate penetrance?4

GENE SELECTEDReported breast cancer associationAssociated with other cancer syndromesDNA repair pathwaysRendering a breast cancerrisk association plausible

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Participant Accrual198 were randomly selected From 654 research samples for study participation; 174 breast cancer57 carried a BRCA1/2 mutationParticipants were representative7

RESULTPathogenic variants in BRCA1/2:57Pathogenic variants in other genes:16 11.4%; 95% CI, 7.0% to 17.7%)VUS Variants of Uncertain Significance:428

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RESULT

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RESULTATM (2 women),BLM (1 woman), CDH1 (1 woman), CDKN2A (1 woman),MLH1(1 woman),MUTYH(1 women),NBN(2 women),PRSS1(1 woman),SLX4 (2 women).

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VUS Variants of Uncertain SignificanceA total of 428 VUS were identified in 39 genes among 175 participants. Per participant, the average number of VUS across all genes was 2.111

RESULTStudies of multigene panel for hereditary cancersReferenceNSubjectsPanel genes1 Cancer 121, 25-33 (2015)2158BC referred for BRCA gene testing252 Genet Med 16, 830-837 (2014)2079hereditary cancer14-223 J Clin Oncol 33, 304-311 (2015)1824TNBC174 J Mol Diagn 17, 533-544 (2015)1105HBOC risk assessment under NCCN guideline295 JAMA Oncol (2015)1046non-BRCA HBOC29256 Eur J Hum Genet 22, 1305-1313 (2014)93559 BRCA carriers+874 high-risk317 Gynecol Oncol 137, 86-92 (2015)911BC/OC218 J Clin Oncol 33, 2015 (suppl; abstr 1511)810non-BRCA BC with high-risk features209 Proc Natl Acad Sci U S A 108, 18032-18037 (2011)360primary ovarian, peritoneal, or fallopian tube carcinoma2110 Ann Surg Oncol 22, 3282-3288 (2015)337629 underwent limited BRCA1/2 testing and337 patients underwent panel testing5-4311 Genet Med 17, 630-638 (2015)278non-BRCA BC with early-onset2212 J Clin Oncol 32, 2001-2009 (2014)231174 BC+57 BRCA carriers4213 FEBS J 282, 3424-3437 (2015)104non-BRCA BC3121 Gastroenterology 149, 604-613 e620 (2015)1260clinical genetic testing for Lynch syndrome252 Gastroenterology 148, 556-564 (2015)708pancreatic cancers133 J Clin Oncol 33, 426-432 (2015)626early-onset familial CRC512