@article {848, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17\% to 78\% for coronary artery disease, 13\% to 76\% for breast cancer, and 11\% to 80\% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {206, title = {Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.}, journal = {Cancer Discov}, volume = {5}, year = {2015}, month = {2015 Feb}, pages = {135-42}, abstract = {

UNLABELLED: Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).

SIGNIFICANCE: We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.

}, keywords = {Adult, Alleles, Base Sequence, BRCA1 Protein, Breast Neoplasms, Fanconi Anemia, Fanconi Anemia Complementation Group Proteins, Female, Genes, BRCA1, Genetic Predisposition to Disease, Humans, Mutation, Young Adult}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-14-1156}, author = {Sawyer, Sarah L and Tian, Lei and K{\"a}hk{\"o}nen, Marketta and Schwartzentruber, Jeremy and Kircher, Martin and Majewski, Jacek and Dyment, David A and Innes, A Micheil and Boycott, Kym M and Moreau, Lisa A and Moilanen, Jukka S and Greenberg, Roger A} } @article {280, title = {Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer.}, journal = {Anesthesiology}, volume = {119}, year = {2013}, month = {2013 Dec}, pages = {1422-33}, abstract = {

BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort.

METHODS: Intensity of cold (+2-4{\textdegree}C) and heat (+48{\textdegree}C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression.

RESULTS: There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found.

CONCLUSIONS: SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied.

}, keywords = {Acute Pain, Adult, Aged, Analgesics, Opioid, Anesthesia, Breast Neoplasms, Catechol O-Methyltransferase, Cold Temperature, Databases, Genetic, Female, Follow-Up Studies, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Hot Temperature, Humans, Middle Aged, Oxycodone, Pain Measurement, Pain, Postoperative, Polymorphism, Single Nucleotide}, issn = {1528-1175}, doi = {10.1097/ALN.0000000000000013}, author = {Kambur, Oleg and Kaunisto, Mari A and Tikkanen, Emmi and Leal, Suzanne M and Ripatti, Samuli and Kalso, Eija A} }