Dataset Information

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

ABSTRACT:

Background

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.

Methods

We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.

Results

For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10^-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10^-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.

Conclusions

This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

SUBMITTER: Southey MC

PROVIDER: S-EPMC5200636 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Southey Melissa C MC Goldgar David E DE Winqvist Robert R Pylkäs Katri K Couch Fergus F Tischkowitz Marc M Foulkes William D WD Dennis Joe J Michailidou Kyriaki K van Rensburg Elizabeth J EJ Heikkinen Tuomas T Nevanlinna Heli H Hopper John L JL Dörk Thilo T Claes Kathleen Bm KB Reis-Filho Jorge J Teo Zhi Ling ZL Radice Paolo P Catucci Irene I Peterlongo Paolo P Tsimiklis Helen H Odefrey Fabrice A FA Dowty James G JG Schmidt Marjanka K MK Broeks Annegien A Hogervorst Frans B FB Verhoef Senno S Carpenter Jane J Clarke Christine C Scott Rodney J RJ Fasching Peter A PA Haeberle Lothar L Ekici Arif B AB Beckmann Matthias W MW Peto Julian J Dos-Santos-Silva Isabel I Fletcher Olivia O Johnson Nichola N Bolla Manjeet K MK Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Marme Federik F Burwinkel Barbara B Yang Rongxi R Guénel Pascal P Truong Thérèse T Menegaux Florence F Sanchez Marie M Bojesen Stig S Nielsen Sune F SF Flyger Henrik H Benitez Javier J Zamora M Pilar MP Perez Jose Ignacio Arias JI Menéndez Primitiva P Anton-Culver Hoda H Neuhausen Susan S Ziogas Argyrios A Clarke Christina A CA Brenner Hermann H Arndt Volker V Stegmaier Christa C Brauch Hiltrud H Brüning Thomas T Ko Yon-Dschun YD Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Bogdanova Natalia V NV Antonenkova Natalia N NN Lindblom Annika A Margolin Sara S Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Spurdle Amanda B AB Investigators kConFab K Wauters Els E Smeets Dominiek D Beuselinck Benoit B Floris Giuseppe G Chang-Claude Jenny J Rudolph Anja A Seibold Petra P Flesch-Janys Dieter D Olson Janet E JE Vachon Celine C Pankratz Vernon S VS McLean Catriona C Haiman Christopher A CA Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Kristensen Vessela V Alnæs Grethe Grenaker GG Zheng Wei W Hunter David J DJ Lindstrom Sara S Hankinson Susan E SE Kraft Peter P Andrulis Irene I Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Jukkola-Vuorinen Arja A Grip Mervi M Kauppila Saila S Devilee Peter P Tollenaar Robert A E M RA Seynaeve Caroline C Hollestelle Antoinette A Garcia-Closas Montserrat M Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Czene Kamila K Darabi Hatef H Eriksson Mikael M Eccles Diana M DM Rafiq Sajjad S Tapper William J WJ Gerty Sue M SM Hooning Maartje J MJ Martens John W M JW Collée J Margriet JM Tilanus-Linthorst Madeleine M Hall Per P Li Jingmei J Brand Judith S JS Humphreys Keith K Cox Angela A Reed Malcolm W R MW Luccarini Craig C Baynes Caroline C Dunning Alison M AM Hamann Ute U Torres Diana D Ulmer Hans Ulrich HU Rüdiger Thomas T Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Slager Susan S Toland Amanda E AE Ambrosone Christine B CB Yannoukakos Drakoulis D Swerdlow Anthony A Ashworth Alan A Orr Nick N Jones Michael M González-Neira Anna A Pita Guillermo G Alonso M Rosario MR Álvarez Nuria N Herrero Daniel D Tessier Daniel C DC Vincent Daniel D Bacot Francois F Simard Jacques J Dumont Martine M Soucy Penny P Eeles Rosalind R Muir Kenneth K Wiklund Fredrik F Gronberg Henrik H Schleutker Johanna J Nordestgaard Børge G BG Weischer Maren M Travis Ruth C RC Neal David D Donovan Jenny L JL Hamdy Freddie C FC Khaw Kay-Tee KT Stanford Janet L JL Blot William J WJ Thibodeau Stephen S Schaid Daniel J DJ Kelley Joseph L JL Maier Christiane C Kibel Adam S AS Cybulski Cezary C Cannon-Albright Lisa L Butterbach Katja K Park Jong J Kaneva Radka R Batra Jyotsna J Teixeira Manuel R MR Kote-Jarai Zsofia Z Olama Ali Amin Al AA Benlloch Sara S Renner Stefan P SP Hartmann Arndt A Hein Alexander A Ruebner Matthias M Lambrechts Diether D Van Nieuwenhuysen Els E Vergote Ignace I Lambretchs Sandrina S Doherty Jennifer A JA Rossing Mary Anne MA Nickels Stefan S Eilber Ursula U Wang-Gohrke Shan S Odunsi Kunle K Sucheston-Campbell Lara E LE Friel Grace G Lurie Galina G Killeen Jeffrey L JL Wilkens Lynne R LR Goodman Marc T MT Runnebaum Ingo I Hillemanns Peter A PA Pelttari Liisa M LM Butzow Ralf R Modugno Francesmary F Edwards Robert P RP Ness Roberta B RB Moysich Kirsten B KB du Bois Andreas A Heitz Florian F Harter Philipp P Kommoss Stefan S Karlan Beth Y BY Walsh Christine C Lester Jenny J Jensen Allan A Kjaer Susanne Krüger SK Høgdall Estrid E Peissel Bernard B Bonanni Bernardo B Bernard Loris L Goode Ellen L EL Fridley Brooke L BL Vierkant Robert A RA Cunningham Julie M JM Larson Melissa C MC Fogarty Zachary C ZC Kalli Kimberly R KR Liang Dong D Lu Karen H KH Hildebrandt Michelle A T MA Wu Xifeng X Levine Douglas A DA Dao Fanny F Bisogna Maria M Berchuck Andrew A Iversen Edwin S ES Marks Jeffrey R JR Akushevich Lucy L Cramer Daniel W DW Schildkraut Joellen J Terry Kathryn L KL Poole Elizabeth M EM Stampfer Meir M Tworoger Shelley S SS Bandera Elisa V EV Orlow Irene I Olson Sara H SH Bjorge Line L Salvesen Helga B HB van Altena Anne M AM Aben Katja K H KK Kiemeney Lambertus A LA Massuger Leon F A G LF Pejovic Tanja T Bean Yukie Y Brooks-Wilson Angela A Kelemen Linda E LE Cook Linda S LS Le Nhu D ND Górski Bohdan B Gronwald Jacek J Menkiszak Janusz J Høgdall Claus K CK Lundvall Lene L Nedergaard Lotte L Engelholm Svend Aage SA Dicks Ed E Tyrer Jonathan J Campbell Ian I McNeish Iain I Paul James J Siddiqui Nadeem N Glasspool Rosalind R Whittemore Alice S AS Rothstein Joseph H JH McGuire Valerie V Sieh Weiva W Cai Hui H Shu Xiao-Ou XO Teten Rachel T RT Sutphen Rebecca R McLaughlin John R JR Narod Steven A SA Phelan Catherine M CM Monteiro Alvaro N AN Fenstermacher David D Lin Hui-Yi HY Permuth Jennifer B JB Sellers Thomas A TA Chen Y Ann YA Tsai Ya-Yu YY Chen Zhihua Z Gentry-Maharaj Aleksandra A Gayther Simon A SA Ramus Susan J SJ Menon Usha U Wu Anna H AH Pearce Celeste L CL Van Den Berg David D Pike Malcolm C MC Dansonka-Mieszkowska Agnieszka A Plisiecka-Halasa Joanna J Moes-Sosnowska Joanna J Kupryjanczyk Jolanta J Pharoah Paul Dp PD Song Honglin H Winship Ingrid I Chenevix-Trench Georgia G Giles Graham G GG Tavtigian Sean V SV Easton Doug F DF Milne Roger L RL

Journal of medical genetics 20160905 12

<h4>Background</h4>The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.<h4>Methods</h4>We genotyped 10 rare muta ...[more]

PMID: 27595995

Similar Datasets

Project description:ImportanceScreening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women.ObjectiveTo estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants.Design, setting, and participantsThis comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985.InterventionsScreening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years.Main outcomes and measuresEstimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges.ResultsThe mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women.Conclusions and relevanceThis analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

Dataset Information

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Background

Methods

Results

Conclusions

Publications

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets