Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

Emma R. Woodward; Elke M. van Veen; Claire Forde; Elaine F. Harkness; Helen J. Byers; Jamie M. Ellingford; George J. Burghel; Helene Schlech; Naomi L. Bowers; Andrew J. Wallace; Sacha J. Howell; Anthony Howell; Fiona Lalloo; William G. Newman; Miriam J. Smith; D. Gareth Evans

doi:10.1038/s41436-021-01234-6

Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

Emma R. Woodward
, Elke M. van Veen
, Claire Forde
, Elaine F. Harkness
, Helen J. Byers
, Jamie M. Ellingford
, George J. Burghel
, Helene Schlech
, Naomi L. Bowers
, Andrew J. Wallace
, Sacha J. Howell
, Anthony Howell
, Fiona Lalloo
, William G. Newman
, Miriam J. Smith
, D. Gareth Evans^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial non-mucinous ovarian cancer and 1567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results: 35 PALB2 and 44 CHEK2_1100delC PGVs were detected in patients [odds ratio (OR) PALB2 breast-ovarian=5.90 (95% CIs:1.92-18.36), CHEK2 breast-ovarian=4.46 (95% CIs:1.86-10.46); PALB2 breast=6.16 (95% CIs:1.98-19.21), CHEK2 breast=4.89 (95% CIs:2.01-11.34). Grade3-ERpositive-HER2negative, grade3 and triple negative (TN) tumours were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service [respectively: 15/43, 254/1843, P=0.0005; 28/37, 562/1381, P=0.0001; 12/43, 204/1639, P<0.0001). PALB2_PGV likelihood increased with increasing Manchester Score (MS) [MS<15=17/1763, MS 20-39=11/520, P=0.04] but not for CHEK2_1100delC [MS<15=29/1762, MS 20-39=4/520]. PALB2 PGVs showed perfect segregation in 20/20 first degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P=0.002). Conclusion: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade3, TN and grade3-ERpositive-HER2negative breast tumours.

Original language	English
Pages (from-to)	1969-1976
Journal	Genetics in Medicine
Volume	23
Issue number	10
DOIs	https://doi.org/10.1038/s41436-021-01234-6
Publication status	Published - 1 Oct 2021

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10.1038/s41436-021-01234-6Licence: CC BY

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Woodward, E. R., van Veen, E. M., Forde, C., Harkness, E. F., Byers, H. J., Ellingford, J. M., Burghel, G. J., Schlech, H., Bowers, N. L., Wallace, A. J., Howell, S. J., Howell, A., Lalloo, F., Newman, W. G., Smith, M. J., & Evans, D. G. (2021). Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer. Genetics in Medicine, 23(10), 1969-1976. https://doi.org/10.1038/s41436-021-01234-6

@article{dfcb5e129089441d84acdc86b0ff2f74,

title = "Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer",

abstract = "Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2\_PGV) and the CHEK2 c.1100delC (CHEK2\_1100delC) PGV to familial breast and ovarian cancer, and PALB2\_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2\_PGV and CHEK2\_1100delC testing were recorded in 3127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial non-mucinous ovarian cancer and 1567 female controls. Breast cancer pathology was recorded in PALB2\_PGV cases from extended families. Results: 35 PALB2 and 44 CHEK2\_1100delC PGVs were detected in patients [odds ratio (OR) PALB2 breast-ovarian=5.90 (95\% CIs:1.92-18.36), CHEK2 breast-ovarian=4.46 (95\% CIs:1.86-10.46); PALB2 breast=6.16 (95\% CIs:1.98-19.21), CHEK2 breast=4.89 (95\% CIs:2.01-11.34). Grade3-ERpositive-HER2negative, grade3 and triple negative (TN) tumours were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service [respectively: 15/43, 254/1843, P=0.0005; 28/37, 562/1381, P=0.0001; 12/43, 204/1639, P<0.0001). PALB2\_PGV likelihood increased with increasing Manchester Score (MS) [MS<15=17/1763, MS 20-39=11/520, P=0.04] but not for CHEK2\_1100delC [MS<15=29/1762, MS 20-39=4/520]. PALB2 PGVs showed perfect segregation in 20/20 first degree relatives with breast cancer, compared with 7/13 for CHEK2\_1100delC (P=0.002). Conclusion: PALB2 PGVs and CHEK2\_1100delC together account for \textasciitilde{}2.5\% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade3, TN and grade3-ERpositive-HER2negative breast tumours. ",

author = "Woodward, \{Emma R.\} and \{van Veen\}, \{Elke M.\} and Claire Forde and Harkness, \{Elaine F.\} and Byers, \{Helen J.\} and Ellingford, \{Jamie M.\} and Burghel, \{George J.\} and Helene Schlech and Bowers, \{Naomi L.\} and Wallace, \{Andrew J.\} and Howell, \{Sacha J.\} and Anthony Howell and Fiona Lalloo and Newman, \{William G.\} and Smith, \{Miriam J.\} and Evans, \{D. Gareth\}",

year = "2021",

month = oct,

day = "1",

doi = "10.1038/s41436-021-01234-6",

language = "English",

volume = "23",

pages = "1969--1976",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier BV",

number = "10",

}

Woodward, ER, van Veen, EM, Forde, C, Harkness, EF , Byers, HJ , Ellingford, JM, Burghel, GJ, Schlech, H, Bowers, NL, Wallace, AJ, Howell, SJ , Howell, A, Lalloo, F, Newman, WG, Smith, MJ & Evans, DG 2021, 'Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer', Genetics in Medicine, vol. 23, no. 10, pp. 1969-1976. https://doi.org/10.1038/s41436-021-01234-6

TY - JOUR

T1 - Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

AU - Woodward, Emma R.

AU - van Veen, Elke M.

AU - Forde, Claire

AU - Harkness, Elaine F.

AU - Byers, Helen J.

AU - Ellingford, Jamie M.

AU - Burghel, George J.

AU - Schlech, Helene

AU - Bowers, Naomi L.

AU - Wallace, Andrew J.

AU - Howell, Sacha J.

AU - Howell, Anthony

AU - Lalloo, Fiona

AU - Newman, William G.

AU - Smith, Miriam J.

AU - Evans, D. Gareth

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial non-mucinous ovarian cancer and 1567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results: 35 PALB2 and 44 CHEK2_1100delC PGVs were detected in patients [odds ratio (OR) PALB2 breast-ovarian=5.90 (95% CIs:1.92-18.36), CHEK2 breast-ovarian=4.46 (95% CIs:1.86-10.46); PALB2 breast=6.16 (95% CIs:1.98-19.21), CHEK2 breast=4.89 (95% CIs:2.01-11.34). Grade3-ERpositive-HER2negative, grade3 and triple negative (TN) tumours were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service [respectively: 15/43, 254/1843, P=0.0005; 28/37, 562/1381, P=0.0001; 12/43, 204/1639, P<0.0001). PALB2_PGV likelihood increased with increasing Manchester Score (MS) [MS<15=17/1763, MS 20-39=11/520, P=0.04] but not for CHEK2_1100delC [MS<15=29/1762, MS 20-39=4/520]. PALB2 PGVs showed perfect segregation in 20/20 first degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P=0.002). Conclusion: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade3, TN and grade3-ERpositive-HER2negative breast tumours.

AB - Purpose: To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Methods: Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial non-mucinous ovarian cancer and 1567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Results: 35 PALB2 and 44 CHEK2_1100delC PGVs were detected in patients [odds ratio (OR) PALB2 breast-ovarian=5.90 (95% CIs:1.92-18.36), CHEK2 breast-ovarian=4.46 (95% CIs:1.86-10.46); PALB2 breast=6.16 (95% CIs:1.98-19.21), CHEK2 breast=4.89 (95% CIs:2.01-11.34). Grade3-ERpositive-HER2negative, grade3 and triple negative (TN) tumours were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service [respectively: 15/43, 254/1843, P=0.0005; 28/37, 562/1381, P=0.0001; 12/43, 204/1639, P<0.0001). PALB2_PGV likelihood increased with increasing Manchester Score (MS) [MS<15=17/1763, MS 20-39=11/520, P=0.04] but not for CHEK2_1100delC [MS<15=29/1762, MS 20-39=4/520]. PALB2 PGVs showed perfect segregation in 20/20 first degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P=0.002). Conclusion: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade3, TN and grade3-ERpositive-HER2negative breast tumours.

U2 - 10.1038/s41436-021-01234-6

DO - 10.1038/s41436-021-01234-6

M3 - Article

SN - 1098-3600

VL - 23

SP - 1969

EP - 1976

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

ER -

Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

Abstract

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