Author
Annika Lindblom
Other affiliations: Karolinska University Hospital, Malmö University
Bio: Annika Lindblom is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Genome-wide association study & Breast cancer. The author has an hindex of 10, co-authored 16 publications receiving 573 citations. Previous affiliations of Annika Lindblom include Karolinska University Hospital & Malmö University.
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TL;DR: A genome-wide association study including 133,384 breast cancer cases and 113,789 controls plus 18,908 BRCA1 mutation carriers of European ancestry provides an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
190 citations
Stephanie L. Schmit, Christopher K. Edlund, Fredrick R. Schumacher, Jian Gong +195 more•Institutions (77)
TL;DR: This article identified 42 loci (P < 5x10−8) associated with risk of colorectal cancer (CRC) and expanded consortium efforts facilitating the discovery of these loci.
Abstract: Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5x10(-8)) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the d ...
131 citations
TL;DR: An expression-based strategy stratified the present "mutation-negative" cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 and those likely to be associated with other, as yet unknown susceptibility genes.
Abstract: Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families. Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced. Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated...
106 citations
TL;DR: A genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers of European ancestry provides an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P
102 citations
TL;DR: It is concluded that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome‐like patients is both feasible and desirable.
Abstract: Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and I I endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G > T, c.736-741del6ins11, c.862_863del, c.1688G > T, and c.2007-IG > A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable. (Less)
94 citations
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TL;DR: One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance, but IHC is more readily available and helps to direct gene testing.
Abstract: Purpose Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.
789 citations
TL;DR: Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.
Abstract: High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.
630 citations
TL;DR: Over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome are chronicle, beginning in 1895 with Warthin's observations of familial cancer clusters.
Abstract: Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
585 citations
TL;DR: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes.
495 citations
Mayo Clinic1, National Institutes of Health2, Harvard University3, Science Applications International Corporation4, New York University5, Utrecht University6, University of Toronto7, University of Minnesota8, Mercy Medical Center (Baltimore, Maryland)9, University of California, San Francisco10, American Cancer Society11, Johns Hopkins University12, Fred Hutchinson Cancer Research Center13, University of Texas MD Anderson Cancer Center14, Yale University15, Vanderbilt University16, University of Paris-Sud17, German Cancer Research Center18, Veterans Health Administration19, Umeå University20, Georgetown University21, Memorial Sloan Kettering Cancer Center22, University of Pittsburgh23, Imperial College London24, French Institute of Health and Medical Research25, Academy of Athens26, Kaiser Permanente27, National Institute for Health and Welfare28, University at Buffalo29, Group Health Cooperative30
TL;DR: This study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies and identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.1 that are associated with multiple cancers.
Abstract: We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
494 citations