Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases. © 2001 Cancer Research Campaign http://www.bjcancer.co

BACH1 Ser919Pro variant and breast cancer risk

BACKGROUND: BACH1 (BRCA1-associated C-terminal helicase 1; also known as BRCA1-interacting protein 1, BRIP1) is a helicase protein that interacts in vivo with BRCA1, the protein product of one of the major genes for hereditary predisposition to breast cancer. Previously, two BACH1 germ line missense mutations have been identified in early-onset breast cancer patients with and without family history of breast and ovarian cancer. In this study, we aimed to evaluate whether there are BACH1 genetic variants that contribute to breast cancer risk in Finland. METHODS: The BACH1 gene was screened for germ line alterations among probands from 43 Finnish BRCA1/2 negative breast cancer families. Recently, one of the observed common variants, Ser-allele of the Ser919Pro polymorphism, was suggested to associate with an increased breast cancer risk, and was here evaluated in an independent, large series of 888 unselected breast cancer patients and in 736 healthy controls. RESULTS: Six BACH1 germ line alterations were observed in the mutation analysis, but none of these were found to associate with the cancer phenotype. The Val193Ile variant that was seen in only one family was further screened in an independent series of 346 familial breast cancer cases and 183 healthy controls, but no additional carriers were observed. Individuals with the BACH1 Ser919-allele were not found to have an increased breast cancer risk when the Pro/Ser heterozygotes (OR 0.90; 95% CI 0.70–1.16; p = 0.427) or Ser/Ser homozygotes (OR 1.02; 95% CI 0.76–1.35; p = 0.91) were compared to Pro/Pro homozygotes, and there was no association of the variant with any breast tumor characteristics, age at cancer diagnosis, family history of cancer, or survival. CONCLUSION: Our results suggest that the BACH1 Ser919 is not a breast cancer predisposition allele in the Finnish study population. Together with previous studies, our results also indicate that although some rare germ line variants in BACH1 may contribute to breast cancer development, the contribution of BACH1 germline alterations to familial breast cancer seems marginal

Comprehensive analysis of NuMA variation in breast cancer

<p>Abstract</p> <p>Background</p> <p>A recent genome wide case-control association study identified <it>NuMA </it>region on 11q13 as a candidate locus for breast cancer susceptibility. Specifically, the variant Ala794Gly was suggested to be associated with increased risk of breast cancer.</p> <p>Methods</p> <p>In order to evaluate the <it>NuMa </it>gene for breast cancer susceptibility, we have here screened the entire coding region and exon-intron boundaries of <it>NuMa </it>in 92 familial breast cancer patients and constructed haplotypes of the identified variants. Five missense variants were further screened in 341 breast cancer cases with a positive family history and 368 controls. We examined the frequency of Ala794Gly in an extensive series of familial (n = 910) and unselected (n = 884) breast cancer cases and controls (n = 906), with a high power to detect the suggested breast cancer risk. We also tested if the variant is associated with histopathologic features of breast tumors.</p> <p>Results</p> <p>Screening of <it>NuMA </it>resulted in identification of 11 exonic variants and 12 variants in introns or untranslated regions. Five missense variants that were further screened in breast cancer cases with a positive family history and controls, were each carried on a unique haplotype. None of the variants, or the haplotypes represented by them, was associated with breast cancer risk although due to low power in this analysis, very low risk alleles may go unrecognized. The <it>NuMA </it>Ala794Gly showed no difference in frequency in the unselected breast cancer case series or familial case series compared to control cases. Furthermore, Ala794Gly did not show any significant association with histopathologic characteristics of the tumors, though Ala794Gly was slightly more frequent among unselected cases with lymph node involvement.</p> <p>Conclusion</p> <p>Our results do not support the role of <it>NuMA </it>variants as breast cancer susceptibility alleles.</p

Frequency of CHEK2 mutations in a population based, case–control study of breast cancer in young women

INTRODUCTION: The cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC has been associated with increased risk for breast or prostate cancer. Multiple studies have found an elevated frequency of the 1100delC variant in specific stratifications of breast cancer patients with a family history of the disease, including BRCA1/BRCA2 negative families and families with a history of bilateral disease or male breast cancer. However, the 1100delC mutation has only been investigated in a few population-based studies and none from North America. METHODS: We report here on the frequency of three CHEK2 variants that alter protein function – 1100delC, R145W, and I175T – in 506 cases and 459 controls from a population based, case–control study of breast cancer conducted in young women from western Washington. RESULTS: There was a suggestive enrichment in the 1100delC variant in the cases (1.2%) as compared with the controls (0.4%), but this was based on small numbers of carriers and the differences were not statistically significant. The 1100delC variant was more frequent in cases with a first-degree family history of breast cancer (4.3%; P = 0.02) and slightly enriched in cases with a family history of ovarian cancer (4.4%; P = 0.09). CONCLUSION: The CHEK2 variants are rare in the western Washington population and, based on accumulated evidence across studies, are unlikely to be major breast cancer susceptibility genes. Thus, screening for the 1100delC variant may have limited usefulness in breast cancer prevention programs in the USA

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

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

Association of rare MSH6 variants with familial breast cancer

Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the CHEK2 1100delC mutation present in almost one-fifth of the families-again in a polygenic setting. In order to evaluate the involvement of MSH6 in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire MSH6 coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare MSH6 variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare MSH6 variants are associated with HBCC breast cancer (P <or = 0.00001). However, screening of the entire MSH6 coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. approximately 1.4% in controls, P <or = 0.001), suggesting that rare MSH6 variants are not confined to HBCC breast cancer. Together, our data suggest that rare MSH6 variants may predispose to familial breast cancer. However, none of the rare MSH6 variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesi

ATM variants and cancer risk in breast cancer patients from Southern Finland

BACKGROUND: Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. METHODS: Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. RESULTS: Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. CONCLUSION: Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer