Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Tuesday, May 24, 2016

Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women



2016 ASCO Annual Meeting Abstracts
 Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women.

Sub-category:
Ovarian Cancer
Category:
Gynecologic Cancer
Meeting:
2016 ASCO Annual Meeting
Abstract No:
5510



Abstract:
Background: Multiple-gene germline sequencing panels are increasingly used to assess hereditary cancer risk, yet the magnitude of OC risk is not well defined for many genes on clinically available panels.  

Methods: 95,561 women were tested clinically for hereditary cancer risk with a panel of 25 genes: APC, ATM, BARD1, BMPR1A, BRCA1/2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Patients who had single- or founder-site testing, or prior BRCA1/2 testing, were excluded. Multivariable regression analysis was used to examine the association between pathogenic/suspected pathogenic mutations and personal OC history (Hx) (dependent variable). Independent variables were age, personal/family cancer Hx, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant.  

Results: Mutations were detected in 6,775/95,561 (7%) patients, of which 3,007 (44%) were in BRCA1/2 and 3,768 (56%) in other genes. A significant association with personal OC Hx was found for ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C and RAD51D (Table).  

Conclusions: Among nearly 100,000 women tested clinically for hereditary cancer risk, multiple-gene sequencing detected OC-associated mutations in 11 genes. Gene-specific estimates ranged from two (ATM, BRIP1, NBN, MSH2, MSH6) to > 10 (BRCA1, STK11) fold elevation in OC risk. These results inform the estimation of OC risk with mutations in 25 clinically tested genes.

(OR+ odds ratio)
GeneOR (95%CI) for OC
STK1141.9 (5.55, 315)
BRCA111.8 (9.99, 14.0)
BRCA25.26 (4.38, 6.31)
RAD51C4.98 (3.09, 8.04)
RAD51D4.78 (2.13, 10.7)
MLH13.11 (1.47, 6.59)
BRIP12.62 (1.72, 3.98)
MSH22.04 (1.08, 3.84)
MSH61.92 (1.19, 3.10)
NBN1.85 (1.05, 3.24)
ATM1.69 (1.19, 2.40)
PALB21.60 (0.98, 2.60)
PMS21.57 (0.94, 2.60)
CHEK20.86 (0.56, 1.33)
TP530.66 (0.05, 8.68)
CDH10.63 (0.08, 4.93)
BARD10.59 (0.21, 1.68)
P160.56 (0.12, 2.53)
APC0.36 (0.05, 2.77)
MYH0.40 (0.05, 3.26)
BMPR1A*
CDK4*
P14ARF*
PTEN*
SMAD4*
*Could not be estimated





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