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PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
0022-2593
800-811
Southey, Melissa C.
56062dff-748c-47e4-99f5-044cff9da594
Goldgar, David E.
102af7b6-41ab-46c0-9d76-43359c897e2e
Winqvist, Robert
ed895c41-7b34-49d8-82cf-fa4554b9312a
Eccles, Diana M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Gerty, Susan M.
b2013815-27c9-4a7d-ad42-071f60a8000f
et al.
Southey, Melissa C.
56062dff-748c-47e4-99f5-044cff9da594
Goldgar, David E.
102af7b6-41ab-46c0-9d76-43359c897e2e
Winqvist, Robert
ed895c41-7b34-49d8-82cf-fa4554b9312a
Eccles, Diana M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Rafiq, Sajjad
54722709-929f-4faa-b4d9-863d4d563056
Tapper, William
9d5ddc92-a8dd-4c78-ac67-c5867b62724c
Gerty, Susan M.
b2013815-27c9-4a7d-ad42-071f60a8000f

Southey, Melissa C., Goldgar, David E. and Winqvist, Robert , et al. (2016) PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics, 53 (12), 800-811. (doi:10.1136/jmedgenet-2016-103839).

Record type: Article

Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

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Accepted/In Press date: 21 June 2016
e-pub ahead of print date: 5 September 2016
Published date: 1 December 2016
Organisations: Cancer Sciences, Human Development & Health

Identifiers

Local EPrints ID: 410446
URI: http://eprints.soton.ac.uk/id/eprint/410446
ISSN: 0022-2593
PURE UUID: 7e76ce71-a66f-42d4-b64a-7286157c45de
ORCID for Diana M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169
ORCID for William Tapper: ORCID iD orcid.org/0000-0002-5896-1889

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Date deposited: 08 Jun 2017 16:31
Last modified: 19 Feb 2021 02:33

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