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. 2011 Feb 28;13(1):R20.
doi: 10.1186/bcr2832.

Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals

Kirsi M Kuusisto  1 , Aleksandra Bebel, Mauno Vihinen, Johanna Schleutker, Satu-Leena Sallinen
Affiliations

Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals

Kirsi M Kuusisto et al. Breast Cancer Res. .

Abstract

Introduction: Two major high-penetrance breast cancer genes, BRCA1 and BRCA2, are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with BRCA1 and BRCA2 increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current BRCA1/2 mutation analysis protocol used in genetic counseling.

Methods: Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).

Results: Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA).

Conclusions: In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.

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Figures

Figure 1
Figure 1
Family 249 pedigree. Family pedigree of the index individual with the identified BRCA1 c.5095C > T variant (same variant was also identified in the daughter of the index individual and in the daughter of the index individual's paternal uncle). Individuals with breast or ovarian cancer with age at diagnosis are marked with black circles. Other cancers are marked in grey and accompanied by age at diagnosis, if known. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Current ages of healthy females are marked if known. Br, breast cancer; Co, colon; Kid, kidney; Mel, melanoma; Ov, ovarian cancer; To, tongue; Ute, uterus.
Figure 2
Figure 2
Family 129 pedigree. Family pedigree of the index individual with the identified CHEK2 c.470T > C and PALB2 c.1676A > G variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Other cancers are marked in grey and accompanied by age at diagnosis, if known. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Bil. Br, bilateral breast cancer; Co, colon; Sto, stomach.
Figure 3
Figure 3
Family 110 pedigree. Family pedigree of the index individual with the identified CHEK2 c.470T > C, c.792 + 39C > T, c.1100delC, and RAD50 c. 2398-32A > G variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Other cancers are marked in grey and accompanied by age at diagnosis, if known. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Current ages of healthy females are marked if known. Br, breast cancer; Ca, cancer with unknown primary site; Pr, prostate.
Figure 4
Figure 4
Family 264 pedigree. Family pedigree of the index individual with the identified CHEK2 c.1100delC variant. Individuals with breast cancer with age at diagnosis are marked with black circles. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Current ages of healthy females are marked if known. Bil. Br, bilateral breast cancer; Br, breast cancer.
Figure 5
Figure 5
Family 265 pedigree. Family pedigree of the index individual with the identified CHEK2 c.1100delC and PALB2 c.1676A > G variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Index individual is marked with an arrow. Current ages of healthy females are marked if known. Br, breast cancer.
Figure 6
Figure 6
Family 262 pedigree. Family pedigree of the index individual with the identified CHEK2 c.470T > C and PALB2 c.1000T > G variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Other cancers are marked in grey and accompanied by age at diagnosis, if known. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Current ages of healthy females are marked if known. Bil. Br, bilateral breast cancer; Br, breast cancer, Panc, pancreas; Si, sigma.
Figure 7
Figure 7
Family 131 pedigree. Family pedigree of the index individual with the identified PALB2 c.1676A > G and BRIP1 c.584T > C variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Current ages of healthy females are marked if known. Bil. Br, bilateral breast cancer; Br, breast cancer.
Figure 8
Figure 8
Family 005 pedigree. Family pedigree of the index individual with the identified BRCA2 c.8182G > A and c.10234A > G variants. Individuals with breast cancer with age at diagnosis are marked with black circles. Other cancers are marked in grey and accompanied by age at diagnosis, if known. Index individual is marked with an arrow. Deceased individuals are indicated with a slash. Bil. Br, bilateral breast cancer; Br, breast cancer; Sto, stomach.
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