Evaluation of variants in the CHEK2, BRIP1 and PALB2 genes in an Irish breast cancer cohort

McInerney, Niall; Miller, Nicola; Rowan, Andrew; Colleran, Gabrielle; Barclay, Ella; Curran, Catherine; Kerin, Michael J.; Tomlinson, Ian; Sawyer, Elinor J.

doi:10.1007/s10549-009-0540-9

Cited by 32 publications

(15 citation statements)

References 32 publications

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“…In this series of patients with ovarian carcinoma, we identified deleterious germ-line mutations in every gene that we evaluated in the Fanconi anemia pathway, including NBN, MRE11, RAD50, RAD51C, PALB2, BARD1, and BRIP1. Mutation rates in these genes in patients with ovarian carcinoma in this series (who were not selected for family history) are similar to rates previously reported for patients with breast cancer from high-incidence families (25)(26)(27)(28). Our data suggest that this pathway is as broadly involved in ovarian carcinogenesis as in breast carcinogenesis.…”

Section: Discussionsupporting

confidence: 88%

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

Walsh

Casadei

Lee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

853

709

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Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost. O varian carcinoma is the most deadly of gynecological malignancies; the majority of women are diagnosed with advanced stage disease when the chance of cure is small. Inherited mutations in BRCA1 and BRCA2 create a lifetime risk of ovarian carcinoma of between 20% (for BRCA2) and 50% or even higher (for BRCA1) (1). It has been previously estimated that 13-15% of patients with ovarian carcinoma in North America carry germ-line mutations in BRCA1 or BRCA2 (2, 3). Hereditary ovarian carcinoma also occurs in the context of Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)], but the proportion of ovarian carcinoma explained by germ-line mutations in the mismatch repair genes has not been determined. Inherited mutations in RAD51C, RAD51D, and PALB2 have also been reported in patients with familial ovarian carcinoma (4-6). The overall proportion of ovarian carcinoma due to germ-line mutations in these genes and the roles of other tumor suppressor genes, particularly those implicated in inherited breast cancer, remain unknown.Women with early stage ovarian carcinoma have far better survival than women whose carcinomas are diagnosed at later stages, but current methods of early detection have not proven effective (7). In contrast, risk-reducing salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations dramatically reduces risk of ovarian carcinoma and significantly decreases overall mortality (8-10). It is critically i...

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Section: Discussionsupporting

confidence: 88%

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

Walsh

Casadei

Lee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

853

709

View full text Add to dashboard Cite

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“…CHEK2 is the most extensively studied of the breast cancer genes after the initially identified BRCA1 and BRCA2 (McInerney et al, 2010). Four CHEK2 mutations have been identified in a cohort of Polish patients, three of which are proteintruncating (del5395, IVS2+1G4A, 1100delC) while the fourth is a common missense variant (I157T) (Cybulski et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The CHEK2 I157T Variant and Breast Cancer Susceptibility: A Systematic Review and Meta-analysis

Liu¹,

Wang²,

Wang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…In total, 77 PALB2 mutation-positive cases have been identified mainly in familial or early onset breast cancer cohorts from different populations [13,15,[18][19][20][21][22][23][24][25]. Of the 77 described PALB2 mutation cases, 52 are carrier of the 1592delT Finnish founder mutation, which could influence the currently known phenotype [19,24,26].…”

Section: Discussionmentioning

confidence: 99%

PALB2 analysis in BRCA2-like families

Adank

Mil

Gille

et al. 2010

Breast Cancer Res Treat

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BRCA2 and PALB2 function together in the Fanconi anemia (FA)-Breast Cancer (BRCA) pathway. Mono-allelic and bi-allelic BRCA2 and PALB2 mutation carriers share many clinical characteristics. Mono-allelic germline mutations of BRCA2 and PALB2 are risk alleles of female breast cancer and have also been reported in familial pancreatic cancer, and bi-allelic mutations cause a severe form of Fanconi anemia. In view of these similarities, we investigated whether the prevalence of PALB2 mutations was increased in breast cancer families with the occurrence of BRCA2 associated tumours other than female breast cancer. PALB2 mutation analysis was performed in 110 non-BRCA1/2 cancer patients: (a) 53 ovarian cancer patients from female breast-and/or ovarian cancer families; (b) 45 breast cancer patients with a first or second degree relative with pancreatic cancer; and (c) 12 male breast cancer patients from female breast cancer families. One truncating PALB2 mutation, c.509_510delGA, resulting in p.Arg170X, was found in a male breast cancer patient. We conclude that germline mutations of PALB2 do not significantly contribute to cancer risk in non-BRCA1/2 cancer families with at least one patient with ovarian cancer, male breast cancer, and/or pancreatic cancer.

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Evaluation of variants in the CHEK2, BRIP1 and PALB2 genes in an Irish breast cancer cohort

Abstract: Background: It has been proposed that rare variants within the double strand break repair genes

Cited by 32 publications

References 32 publications

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing

The CHEK2 I157T Variant and Breast Cancer Susceptibility: A Systematic Review and Meta-analysis

PALB2 analysis in BRCA2-like families

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