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, 38 (7), 674-685

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Xin Yang  1 Goska Leslie  1 Alicja Doroszuk  2 Sandra Schneider  2 Jamie Allen  1 Brennan Decker  1   3   4 Alison M Dunning  5 James Redman  2 James Scarth  2 Inga Plaskocinska  2 Craig Luccarini  5 Mitul Shah  5 Karen Pooley  1 Leila Dorling  1 Andrew Lee  1 Muriel A Adank  6 Julian Adlard  7 Kristiina Aittomäki  8 Irene L Andrulis  9 Peter Ang  10 Julian Barwell  11 Jonine L Bernstein  12 Kristie Bobolis  13 Åke Borg  14 Carl Blomqvist  15 Kathleen B M Claes  16 Patrick Concannon  17 Adeline Cuggia  18   19 Julie O Culver  20 Francesca Damiola  21 Antoine de Pauw  22 Orland Diez  23 Jill S Dolinsky  24 Susan M Domchek  25   26 Christoph Engel  27 D Gareth Evans  28 Florentia Fostira  29 Judy Garber  26   30 Lisa Golmard  22 Ellen L Goode  31 Stephen B Gruber  32 Eric Hahnen  33   34 Christopher Hake  13 Tuomas Heikkinen  35 Judith E Hurley  36 Ramunas Janavicius  37   38 Zdenek Kleibl  39 Petra Kleiblova  39   40 Irene Konstantopoulou  29 Anders Kvist  14 Holly Laduca  24 Ann S G Lee  11   41   42 Fabienne Lesueur  43 Eamonn R Maher  2 Arto Mannermaa  44 Siranoush Manoukian  45 Rachel McFarland  24   46 Wendy McKinnon  47 Alfons Meindl  48 Kelly Metcalfe  49 Nur Aishah Mohd Taib  50 Jukka Moilanen  51 Katherine L Nathanson  25 Susan Neuhausen  52 Pei Sze Ng  50   53 Tu Nguyen-Dumont  54   55 Sarah M Nielsen  56 Florian Obermair  57 Kenneth Offit  26   58 Olufunmilayo I Olopade  56 Laura Ottini  59 Judith Penkert  60 Katri Pylkäs  61 Paolo Radice  62 Susan J Ramus  63   64 Vilius Rudaitis  37 Lucy Side  65 Rachel Silva-Smith  66 Valentina Silvestri  59 Anne-Bine Skytte  67 Thomas Slavin  13   68 Jana Soukupova  39 Carlo Tondini  69 Alison H Trainer  70   71 Gary Unzeitig  13 Lydia Usha  13 Thomas van Overeem Hansen  72   73 James Whitworth  2 Marie Wood  47 Cheng Har Yip  53 Sook-Yee Yoon  53 Amal Yussuf  24 George Zogopoulos  18   19 David Goldgar  74 John L Hopper  75 Georgia Chenevix-Trench  76 Paul Pharoah  1 Sophia H L George  77 Judith Balmaña  23   26 Claude Houdayer  22   78 Paul James  70   71 Zaki El-Haffaf  79 Hans Ehrencrona  80   81 Marketa Janatova  39 Paolo Peterlongo  82 Heli Nevanlinna  35 Rita Schmutzler  33   34 Soo-Hwang Teo  50   53 Mark Robson  26   83 Tuya Pal  84 Fergus Couch  26   85 Jeffrey N Weitzel  13   68 Aaron Elliott  24 Melissa Southey  54   55 Robert Winqvist  61 Douglas F Easton  1 William D Foulkes  18   86 Antonis C Antoniou  1 Marc Tischkowitz  2
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Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Xin Yang et al. J Clin Oncol.

Abstract

Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.

Methods: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

Results: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

Conclusion: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

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