Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

Xin Yang; Goska Leslie; Alicja Doroszuk; Sandra Schneider; Jamie Allen; Brennan Decker; Alison M. Dunning; James Redman; James Scarth; Inga Plaskocinska; Craig Luccarini; Mitul Shah; Karen Pooley; Leila Dorling; Andrew Leei; Muriel A. Adank; Julian Adlard; Kristiina Aittomäki; Irene L. Andrulis; Peter Ang; Julian Barwell; Jonine L. Bernstein; Kristie Bobolis; Åke Borg; Carl Blomqvist; Kathleen B.M. Claes; Patrick Concannon; Adeline Cuggia; Julie O. Culver; Francesca Damiola; Antoine De Pauw; Orland Diez; Jill S. Dolinsky; Susan M. Domchek; Christoph Engel; D. Gareth Evans; Florentia Fostira; Judy Garber; Lisa Golmard; Ellen L. Goode; Stephen B. Gruber; Eric Hahnen; Christopher Hake; Tuomas Heikkinen; Judith E. Hurley; Ramunas Janavicius; Zdenek Kleibl; Petra Kleiblova; Irene Konstantopoulou; Anders Kvist; Holly Laduca; Ann S.G. Lee; Fabienne Lesueur; Eamonn R. Maher; Arto Mannermaa; Siranoush Manoukian; Rachel McFarland; Wendy McKinnon; Alfons Meindl; Kelly Metcalfe; Nur Aishah Mohd Taib; Jukka Moilanen; Katherine L. Nathanson; Susan Neuhausen; Pei Sze Ng; Tu Nguyen-Dumont; Sarah M. Nielsen; Florian Obermair; Kenneth Offit; Olufunmilayo I. Olopade; Laura Ottini; Judith Penkert; Katri Pylkäs; Paolo Radice; Susan J. Ramus; Vilius Rudaitis; Lucy Side; Rachel Silva-Smith; Valentina Silvestri; Anne Bine Skytte; Thomas Slavin; Jana Soukupova; Carlo Tondini; Alison H. Trainer; Gary Unzeitig; Lydia Usha; Thomas Van Overeem Hansen; James Whitworth; Marie Wood; Cheng Har Yip; Sook Yee Yoon; Amal Yussuf; George Zogopoulos; David Goldgar; John L. Hopper; Georgia Chenevix-Trench; Paul Pharoah; Sophia H.L. George; Judith Balmaña; Claude Houdayer; Paul James; Zaki El-Haffaf; Hans Ehrencrona; Marketa Janatova; Paolo Peterlongo; Heli Nevanlinna; Rita Schmutzler; Soo Hwang Teo; Mark Robson; Tuya Pal; Fergus Couch; Jeffrey N. Weitzel; Aaron Elliott; Melissa Southey; Robert Winqvist; Douglas F. Easton; William D. Foulkes; Antonis C. Antoniou; Marc Tischkowitz

doi:10.1200/JCO.19.01907

Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

Xin Yang, Goska Leslie, Alicja Doroszuk, Sandra Schneider, Jamie Allen, Brennan Decker, Alison M. Dunning, James Redman, James Scarth, Inga Plaskocinska, Craig Luccarini, Mitul Shah, Karen Pooley, Leila Dorling, Andrew Leei, Muriel A. Adank, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Peter AngJulian Barwell, Jonine L. Bernstein, Kristie Bobolis, Åke Borg, Carl Blomqvist, Kathleen B.M. Claes, Patrick Concannon, Adeline Cuggia, Julie O. Culver, Francesca Damiola, Antoine De Pauw, Orland Diez, Jill S. Dolinsky, Susan M. Domchek, Christoph Engel, D. Gareth Evans, Florentia Fostira, Judy Garber, Lisa Golmard, Ellen L. Goode, Stephen B. Gruber, Eric Hahnen, Christopher Hake, Tuomas Heikkinen, Judith E. Hurley, Ramunas Janavicius, Zdenek Kleibl, Petra Kleiblova, Irene Konstantopoulou, Anders Kvist, Holly Laduca, Ann S.G. Lee, Fabienne Lesueur, Eamonn R. Maher, Arto Mannermaa, Siranoush Manoukian, Rachel McFarland, Wendy McKinnon, Alfons Meindl, Kelly Metcalfe, Nur Aishah Mohd Taib, Jukka Moilanen, Katherine L. Nathanson, Susan Neuhausen, Pei Sze Ng, Tu Nguyen-Dumont, Sarah M. Nielsen, Florian Obermair, Kenneth Offit, Olufunmilayo I. Olopade, Laura Ottini, Judith Penkert, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Vilius Rudaitis, Lucy Side, Rachel Silva-Smith, Valentina Silvestri, Anne Bine Skytte, Thomas Slavin, Jana Soukupova, Carlo Tondini, Alison H. Trainer, Gary Unzeitig, Lydia Usha, Thomas Van Overeem Hansen, James Whitworth, Marie Wood, Cheng Har Yip, Sook Yee Yoon, Amal Yussuf, George Zogopoulos, David Goldgar, John L. Hopper, Georgia Chenevix-Trench, Paul Pharoah, Sophia H.L. George, Judith Balmaña, Claude Houdayer, Paul James, Zaki El-Haffaf, Hans Ehrencrona, Marketa Janatova, Paolo Peterlongo, Heli Nevanlinna, Rita Schmutzler, Soo Hwang Teo, Mark Robson, Tuya Pal, Fergus Couch, Jeffrey N. Weitzel, Aaron Elliott, Melissa Southey, Robert Winqvist, Douglas F. Easton, William D. Foulkes, Antonis C. Antoniou, Marc Tischkowitz

Medicine Monash Health

Research output: Contribution to journal › Article › Research › peer-review

123 Citations (Scopus)

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 3 1022). 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.

Original language	English
Pages (from-to)	674-685
Number of pages	12
Journal	Journal of Clinical Oncology
Volume	38
Issue number	7
DOIs	https://doi.org/10.1200/JCO.19.01907
Publication status	Published - 1 Mar 2020

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10.1200/JCO.19.01907

Cite this

Yang, X., Leslie, G., Doroszuk, A., Schneider, S., Allen, J., Decker, B., Dunning, A. M., Redman, J., Scarth, J., Plaskocinska, I., Luccarini, C., Shah, M., Pooley, K., Dorling, L., Leei, A., Adank, M. A., Adlard, J., Aittomäki, K., Andrulis, I. L., ... Tischkowitz, M. (2020). Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families. Journal of Clinical Oncology, 38(7), 674-685. https://doi.org/10.1200/JCO.19.01907

Yang, Xin ; Leslie, Goska ; Doroszuk, Alicja ; Schneider, Sandra ; Allen, Jamie ; Decker, Brennan ; Dunning, Alison M. ; Redman, James ; Scarth, James ; Plaskocinska, Inga ; Luccarini, Craig ; Shah, Mitul ; Pooley, Karen ; Dorling, Leila ; Leei, Andrew ; Adank, Muriel A. ; Adlard, Julian ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Ang, Peter ; Barwell, Julian ; Bernstein, Jonine L. ; Bobolis, Kristie ; Borg, Åke ; Blomqvist, Carl ; Claes, Kathleen B.M. ; Concannon, Patrick ; Cuggia, Adeline ; Culver, Julie O. ; Damiola, Francesca ; De Pauw, Antoine ; Diez, Orland ; Dolinsky, Jill S. ; Domchek, Susan M. ; Engel, Christoph ; Evans, D. Gareth ; Fostira, Florentia ; Garber, Judy ; Golmard, Lisa ; Goode, Ellen L. ; Gruber, Stephen B. ; Hahnen, Eric ; Hake, Christopher ; Heikkinen, Tuomas ; Hurley, Judith E. ; Janavicius, Ramunas ; Kleibl, Zdenek ; Kleiblova, Petra ; Konstantopoulou, Irene ; Kvist, Anders ; Laduca, Holly ; Lee, Ann S.G. ; Lesueur, Fabienne ; Maher, Eamonn R. ; Mannermaa, Arto ; Manoukian, Siranoush ; McFarland, Rachel ; McKinnon, Wendy ; Meindl, Alfons ; Metcalfe, Kelly ; Taib, Nur Aishah Mohd ; Moilanen, Jukka ; Nathanson, Katherine L. ; Neuhausen, Susan ; Ng, Pei Sze ; Nguyen-Dumont, Tu ; Nielsen, Sarah M. ; Obermair, Florian ; Offit, Kenneth ; Olopade, Olufunmilayo I. ; Ottini, Laura ; Penkert, Judith ; Pylkäs, Katri ; Radice, Paolo ; Ramus, Susan J. ; Rudaitis, Vilius ; Side, Lucy ; Silva-Smith, Rachel ; Silvestri, Valentina ; Skytte, Anne Bine ; Slavin, Thomas ; Soukupova, Jana ; Tondini, Carlo ; Trainer, Alison H. ; Unzeitig, Gary ; Usha, Lydia ; Van Overeem Hansen, Thomas ; Whitworth, James ; Wood, Marie ; Yip, Cheng Har ; Yoon, Sook Yee ; Yussuf, Amal ; Zogopoulos, George ; Goldgar, David ; Hopper, John L. ; Chenevix-Trench, Georgia ; Pharoah, Paul ; George, Sophia H.L. ; Balmaña, Judith ; Houdayer, Claude ; James, Paul ; El-Haffaf, Zaki ; Ehrencrona, Hans ; Janatova, Marketa ; Peterlongo, Paolo ; Nevanlinna, Heli ; Schmutzler, Rita ; Teo, Soo Hwang ; Robson, Mark ; Pal, Tuya ; Couch, Fergus ; Weitzel, Jeffrey N. ; Elliott, Aaron ; Southey, Melissa ; Winqvist, Robert ; Easton, Douglas F. ; Foulkes, William D. ; Antoniou, Antonis C. ; Tischkowitz, Marc. / Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families. In: Journal of Clinical Oncology. 2020 ; Vol. 38, No. 7. pp. 674-685.

@article{5f2b355ba1f048faa92e399b4deb691b,

title = "Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families",

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 3 1022). 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.",

author = "Xin Yang and Goska Leslie and Alicja Doroszuk and Sandra Schneider and Jamie Allen and Brennan Decker and Dunning, {Alison M.} and James Redman and James Scarth and Inga Plaskocinska and Craig Luccarini and Mitul Shah and Karen Pooley and Leila Dorling and Andrew Leei and Adank, {Muriel A.} and Julian Adlard and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Peter Ang and Julian Barwell and Bernstein, {Jonine L.} and Kristie Bobolis and {\AA}ke Borg and Carl Blomqvist and Claes, {Kathleen B.M.} and Patrick Concannon and Adeline Cuggia and Culver, {Julie O.} and Francesca Damiola and {De Pauw}, Antoine and Orland Diez and Dolinsky, {Jill S.} and Domchek, {Susan M.} and Christoph Engel and Evans, {D. Gareth} and Florentia Fostira and Judy Garber and Lisa Golmard and Goode, {Ellen L.} and Gruber, {Stephen B.} and Eric Hahnen and Christopher Hake and Tuomas Heikkinen and Hurley, {Judith E.} and Ramunas Janavicius and Zdenek Kleibl and Petra Kleiblova and Irene Konstantopoulou and Anders Kvist and Holly Laduca and Lee, {Ann S.G.} and Fabienne Lesueur and Maher, {Eamonn R.} and Arto Mannermaa and Siranoush Manoukian and Rachel McFarland and Wendy McKinnon and Alfons Meindl and Kelly Metcalfe and Taib, {Nur Aishah Mohd} and Jukka Moilanen and Nathanson, {Katherine L.} and Susan Neuhausen and Ng, {Pei Sze} and Tu Nguyen-Dumont and Nielsen, {Sarah M.} and Florian Obermair and Kenneth Offit and Olopade, {Olufunmilayo I.} and Laura Ottini and Judith Penkert and Katri Pylk{\"a}s and Paolo Radice and Ramus, {Susan J.} and Vilius Rudaitis and Lucy Side and Rachel Silva-Smith and Valentina Silvestri and Skytte, {Anne Bine} and Thomas Slavin and Jana Soukupova and Carlo Tondini and Trainer, {Alison H.} and Gary Unzeitig and Lydia Usha and {Van Overeem Hansen}, Thomas and James Whitworth and Marie Wood and Yip, {Cheng Har} and Yoon, {Sook Yee} and Amal Yussuf and George Zogopoulos and David Goldgar and Hopper, {John L.} and Georgia Chenevix-Trench and Paul Pharoah and George, {Sophia H.L.} and Judith Balma{\~n}a and Claude Houdayer and Paul James and Zaki El-Haffaf and Hans Ehrencrona and Marketa Janatova and Paolo Peterlongo and Heli Nevanlinna and Rita Schmutzler and Teo, {Soo Hwang} and Mark Robson and Tuya Pal and Fergus Couch and Weitzel, {Jeffrey N.} and Aaron Elliott and Melissa Southey and Robert Winqvist and Easton, {Douglas F.} and Foulkes, {William D.} and Antoniou, {Antonis C.} and Marc Tischkowitz",

year = "2020",

month = mar,

day = "1",

doi = "10.1200/JCO.19.01907",

language = "English",

volume = "38",

pages = "674--685",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "7",

}

Yang, X, Leslie, G, Doroszuk, A, Schneider, S, Allen, J, Decker, B, Dunning, AM, Redman, J, Scarth, J, Plaskocinska, I, Luccarini, C, Shah, M, Pooley, K, Dorling, L, Leei, A, Adank, MA, Adlard, J, Aittomäki, K, Andrulis, IL, Ang, P, Barwell, J, Bernstein, JL, Bobolis, K, Borg, Å, Blomqvist, C, Claes, KBM, Concannon, P, Cuggia, A, Culver, JO, Damiola, F, De Pauw, A, Diez, O, Dolinsky, JS, Domchek, SM, Engel, C, Evans, DG, Fostira, F, Garber, J, Golmard, L, Goode, EL, Gruber, SB, Hahnen, E, Hake, C, Heikkinen, T, Hurley, JE, Janavicius, R, Kleibl, Z, Kleiblova, P, Konstantopoulou, I, Kvist, A, Laduca, H, Lee, ASG, Lesueur, F, Maher, ER, Mannermaa, A, Manoukian, S, McFarland, R, McKinnon, W, Meindl, A, Metcalfe, K, Taib, NAM, Moilanen, J, Nathanson, KL, Neuhausen, S, Ng, PS, Nguyen-Dumont, T, Nielsen, SM, Obermair, F, Offit, K, Olopade, OI, Ottini, L, Penkert, J, Pylkäs, K, Radice, P, Ramus, SJ, Rudaitis, V, Side, L, Silva-Smith, R, Silvestri, V, Skytte, AB, Slavin, T, Soukupova, J, Tondini, C, Trainer, AH, Unzeitig, G, Usha, L, Van Overeem Hansen, T, Whitworth, J, Wood, M, Yip, CH, Yoon, SY, Yussuf, A, Zogopoulos, G, Goldgar, D, Hopper, JL, Chenevix-Trench, G, Pharoah, P, George, SHL, Balmaña, J, Houdayer, C, James, P, El-Haffaf, Z, Ehrencrona, H, Janatova, M, Peterlongo, P, Nevanlinna, H, Schmutzler, R, Teo, SH, Robson, M, Pal, T, Couch, F, Weitzel, JN, Elliott, A, Southey, M, Winqvist, R, Easton, DF, Foulkes, WD, Antoniou, AC & Tischkowitz, M 2020, 'Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families', Journal of Clinical Oncology, vol. 38, no. 7, pp. 674-685. https://doi.org/10.1200/JCO.19.01907

Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families. / Yang, Xin; Leslie, Goska; Doroszuk, Alicja; Schneider, Sandra; Allen, Jamie; Decker, Brennan; Dunning, Alison M.; Redman, James; Scarth, James; Plaskocinska, Inga; Luccarini, Craig; Shah, Mitul; Pooley, Karen; Dorling, Leila; Leei, Andrew; Adank, Muriel A.; Adlard, Julian; Aittomäki, Kristiina; Andrulis, Irene L.; Ang, Peter; Barwell, Julian; Bernstein, Jonine L.; Bobolis, Kristie; Borg, Åke; Blomqvist, Carl; Claes, Kathleen B.M.; Concannon, Patrick; Cuggia, Adeline; Culver, Julie O.; Damiola, Francesca; De Pauw, Antoine; Diez, Orland; Dolinsky, Jill S.; Domchek, Susan M.; Engel, Christoph; Evans, D. Gareth; Fostira, Florentia; Garber, Judy; Golmard, Lisa; Goode, Ellen L.; Gruber, Stephen B.; Hahnen, Eric; Hake, Christopher; Heikkinen, Tuomas; Hurley, Judith E.; Janavicius, Ramunas; Kleibl, Zdenek; Kleiblova, Petra; Konstantopoulou, Irene; Kvist, Anders; Laduca, Holly; Lee, Ann S.G.; Lesueur, Fabienne; Maher, Eamonn R.; Mannermaa, Arto; Manoukian, Siranoush; McFarland, Rachel; McKinnon, Wendy; Meindl, Alfons; Metcalfe, Kelly; Taib, Nur Aishah Mohd; Moilanen, Jukka; Nathanson, Katherine L.; Neuhausen, Susan; Ng, Pei Sze; Nguyen-Dumont, Tu; Nielsen, Sarah M.; Obermair, Florian; Offit, Kenneth; Olopade, Olufunmilayo I.; Ottini, Laura; Penkert, Judith; Pylkäs, Katri; Radice, Paolo; Ramus, Susan J.; Rudaitis, Vilius; Side, Lucy; Silva-Smith, Rachel; Silvestri, Valentina; Skytte, Anne Bine; Slavin, Thomas; Soukupova, Jana; Tondini, Carlo; Trainer, Alison H.; Unzeitig, Gary; Usha, Lydia; Van Overeem Hansen, Thomas; Whitworth, James; Wood, Marie; Yip, Cheng Har; Yoon, Sook Yee; Yussuf, Amal; Zogopoulos, George; Goldgar, David; Hopper, John L.; Chenevix-Trench, Georgia; Pharoah, Paul; George, Sophia H.L.; Balmaña, Judith; Houdayer, Claude; James, Paul; El-Haffaf, Zaki; Ehrencrona, Hans; Janatova, Marketa; Peterlongo, Paolo; Nevanlinna, Heli; Schmutzler, Rita; Teo, Soo Hwang; Robson, Mark; Pal, Tuya; Couch, Fergus; Weitzel, Jeffrey N.; Elliott, Aaron; Southey, Melissa; Winqvist, Robert; Easton, Douglas F.; Foulkes, William D.; Antoniou, Antonis C.; Tischkowitz, Marc.

In: Journal of Clinical Oncology, Vol. 38, No. 7, 01.03.2020, p. 674-685.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Cancer risks associated with germline PALB2 pathogenic variants

T2 - An international study of 524 families

AU - Yang, Xin

AU - Leslie, Goska

AU - Doroszuk, Alicja

AU - Schneider, Sandra

AU - Allen, Jamie

AU - Decker, Brennan

AU - Dunning, Alison M.

AU - Redman, James

AU - Scarth, James

AU - Plaskocinska, Inga

AU - Luccarini, Craig

AU - Shah, Mitul

AU - Pooley, Karen

AU - Dorling, Leila

AU - Leei, Andrew

AU - Adank, Muriel A.

AU - Adlard, Julian

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Ang, Peter

AU - Barwell, Julian

AU - Bernstein, Jonine L.

AU - Bobolis, Kristie

AU - Borg, Åke

AU - Blomqvist, Carl

AU - Claes, Kathleen B.M.

AU - Concannon, Patrick

AU - Cuggia, Adeline

AU - Culver, Julie O.

AU - Damiola, Francesca

AU - De Pauw, Antoine

AU - Diez, Orland

AU - Dolinsky, Jill S.

AU - Domchek, Susan M.

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Fostira, Florentia

AU - Garber, Judy

AU - Golmard, Lisa

AU - Goode, Ellen L.

AU - Gruber, Stephen B.

AU - Hahnen, Eric

AU - Hake, Christopher

AU - Heikkinen, Tuomas

AU - Hurley, Judith E.

AU - Janavicius, Ramunas

AU - Kleibl, Zdenek

AU - Kleiblova, Petra

AU - Konstantopoulou, Irene

AU - Kvist, Anders

AU - Laduca, Holly

AU - Lee, Ann S.G.

AU - Lesueur, Fabienne

AU - Maher, Eamonn R.

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - McFarland, Rachel

AU - McKinnon, Wendy

AU - Meindl, Alfons

AU - Metcalfe, Kelly

AU - Taib, Nur Aishah Mohd

AU - Moilanen, Jukka

AU - Nathanson, Katherine L.

AU - Neuhausen, Susan

AU - Ng, Pei Sze

AU - Nguyen-Dumont, Tu

AU - Nielsen, Sarah M.

AU - Obermair, Florian

AU - Offit, Kenneth

AU - Olopade, Olufunmilayo I.

AU - Ottini, Laura

AU - Penkert, Judith

AU - Pylkäs, Katri

AU - Radice, Paolo

AU - Ramus, Susan J.

AU - Rudaitis, Vilius

AU - Side, Lucy

AU - Silva-Smith, Rachel

AU - Silvestri, Valentina

AU - Skytte, Anne Bine

AU - Slavin, Thomas

AU - Soukupova, Jana

AU - Tondini, Carlo

AU - Trainer, Alison H.

AU - Unzeitig, Gary

AU - Usha, Lydia

AU - Van Overeem Hansen, Thomas

AU - Whitworth, James

AU - Wood, Marie

AU - Yip, Cheng Har

AU - Yoon, Sook Yee

AU - Yussuf, Amal

AU - Zogopoulos, George

AU - Goldgar, David

AU - Hopper, John L.

AU - Chenevix-Trench, Georgia

AU - Pharoah, Paul

AU - George, Sophia H.L.

AU - Balmaña, Judith

AU - Houdayer, Claude

AU - James, Paul

AU - El-Haffaf, Zaki

AU - Ehrencrona, Hans

AU - Janatova, Marketa

AU - Peterlongo, Paolo

AU - Nevanlinna, Heli

AU - Schmutzler, Rita

AU - Teo, Soo Hwang

AU - Robson, Mark

AU - Pal, Tuya

AU - Couch, Fergus

AU - Weitzel, Jeffrey N.

AU - Elliott, Aaron

AU - Southey, Melissa

AU - Winqvist, Robert

AU - Easton, Douglas F.

AU - Foulkes, William D.

AU - Antoniou, Antonis C.

AU - Tischkowitz, Marc

PY - 2020/3/1

Y1 - 2020/3/1

N2 - 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 3 1022). 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.

AB - 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 3 1022). 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.

UR - http://www.scopus.com/inward/record.url?scp=85080075709&partnerID=8YFLogxK

U2 - 10.1200/JCO.19.01907

DO - 10.1200/JCO.19.01907

M3 - Article

C2 - 31841383

AN - SCOPUS:85080075709

VL - 38

SP - 674

EP - 685

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 7

ER -

Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

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