BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Meeks, Huong; Song, Honglin; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Barrowdale, Daniel; Frost, Debra; McGuffog, Lesley; Ellis, Steve; Feng, Bing‐Jian; Buys, Saundra S.; Hopper, John L.; Southey, Melissa C.; Tesoriero, Andrea; James, Paul; Bruinsma, Fiona; Campbell, Ian; Broeks, Annegien; Schmidt, Marjanka K.; Hogervorst, Frans B.L.; Beckman, Matthias W.; Fasching, Peter A.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Riboli, Elio; Banerjee, Susana; Menon, Usha; Tomlinson, Ian; Burwinkel, Barbara; Hamann, Ute; Marmé, Frederik; Rudolph, Anja; Janavičius, Ramūnas; Tihomirova, Laima; Tung, Nadine; Garber, Judy E.; Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Dorfling, Cecilia M.; Rensburg, Elizabeth J. van; Godwin, Andrew K.; Guénel, Pascal; Truong, Thérèse; Stoppa‐Lyonnet, Dominique; Damiola, Francesca; Mazoyer, Sylvie; Sinilnikova, Olga M.; Isaacs, Claudine; Maugard, Christine M.; Bojesen, Stig E.; Flyger, Henrik; Gerdes, Anne–Marie; Hansen, Thomas van Overeem; Jensen, Allan; Kjær, Susanne K.; Høgdall, Claus; Høgdall, Estrid; Pedersen, Inge Søkilde; Thomassen, Mads; Benı́tez, Javier; González‐Neira, Anna; Osorio, Ana; Hoya, Miguel de la; Segura, Pedro Pérez; Díez, Orland; Lázaro, Conxi; Brunet, Joan; Anton‐Culver, Hoda; Lee, Eunjung; John, Esther M.; Neuhausen, Susan L.; Ding, Yuan Chun; Castillo, Danielle; Weitzel, Jeffrey N.; Ganz, Patricia A.; Nussbaum, Robert L.; Chan, Salina; Karlan, Beth Y.; Lester, Jenny; Wu, Anna H.; Gayther, Simon A.; Ramus, Susan J.; Sieh, Weiva; Whittermore, Alice S.; Monteiro, Alvaro N.A.; Phelan, Catherine M.; Terry, Mary Beth; Piedmonte, Marion; Offit, Kenneth; Robson, Mark E.; Levine, Douglas A.; Moysich, Kirsten B.; Cannioto, Rikki A.; Olson, Sara H.; Daly, Mary B.; Nathanson, Katherine L.; Domchek, Susan M.; Lu, Karen H.; Liang, Dong; Hildebrant, Michelle A T; Ness, Roberta B.; Modugno, Francesmary; Pearce, Leigh; Goodman, Marc T.; Thompson, Pamela J.; Brenner, Hermann; Butterbach, Katja; Meindl, Alfons; Hahnen, Eric; Wappenschmidt, Barbara; Brauch, Hiltrud; Brüning, Thomas; Blomqvist, Carl; Khan, Sofia; Nevanlinna, Heli; Pelttari, Liisa M.; Aittomäki, Kristiina; Bützow, Ralf; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Rantala, Johanna; Kosma, Veli Matti; Mannermaa, Arto; Lambrechts, Diether; Neven, Patrick; Claes, Kathleen; Maerken, Tom Van; Chang‐Claude, Jenny; Flesch-Janys, Dieter; Heitz, Florian; Varon-Mateeva, Raymonda; Peterlongo, Paolo; Radice, Paolo; Viel, Alessandra; Barile, Mônica; Peissel, Bernard; Manoukian, Siranoush; Montagna, Marco; Oliani, Cristina; Peixoto, Ana; Teixeira, Manuel R.; Collavoli, Anita; Hallberg, Emily; Olson, Janet E.; Goode, Ellen L.; Hart, Steven N.; Shimelis, Hermela; Cunningham, Julie M.; Giles, Graham G.; Milne, Roger L.; Healey, Sue; Tucker, Kathy; Haiman, Christopher A.; Henderson, Brian E.; Goldberg, Mark S.; Tischkowitz, Marc; Simard, Jacques; Soucy, Penny; Eccles, Diana; Le, Nhu D.; Børresen-Dale, Anne Lise; Kristensen, Vessela N.; Salvesen, Helga B.; Bjørge, Line; Bandera, Elisa V.; Risch, Harvey A.; Wang, Zheng; Beeghly–Fadiel, Alicia; Cai, Hui; Pylkäs, Katri; Tollenaar, Robert A.E.M.; Ouweland, Ans M W Van Der; Andrulis, Irene L.; Knight, Julia A.; Narod, Steven A.; Devilee, Peter; Winqvist, Robert; Figueroa, Jonine D.; Greene, Mark H.; Phuong, L.; Loud, Jennifer T.; García‐Closas, Montserrat; Schoemaker, Minouk J.; Czene, Kamila; Darabi, Hatef; McNeish, Iain A.; Siddiquil, Nadeem; Glasspool, Rosalind; Kwong, Ava; Park, Sung Sup; Teo, Soo Hwang; Yoon, Sook Yee; Matsuo, Keitaro; Hosono, Satoyo; Woo, Yin Ling; Gao, Yu Tang; Foretová, Lenka; Singer, Christian F.; Rappaport-Feurhauser, Christine; Friedman, Eitan; Laitman, Yael; Rennert, Gad; Imyanitov, Evgeny N.; Hulick, Peter J.; Olopade, Olufunmilayo I.; Senter, Leigha; Olàh, Edith; Doherty, Jennifer A.; Schildkraut, Joellen M.; Koppert, Linetta B.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Cook, Linda S.; Pejović, Tanja; Li, Jingmei; Borg, Åke; Öfverholm, Anna; Rossing, Mary Anne; Wentzensen, Nicolas; Henriksson, Karin; Cox, Angela; Cross, Simon S.; Pasini, Barbara; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubiński, Jan; Gronwald, Jacek; Agnarsson, Bjarni A.; Kupryjańczyk, Jolanta; Moes-Sosnowska, Joanna; Fostira, Florentia; Konstantopoulou, Irene; Slager, Susan L.; Jones, Michael E.; Antoniou, Antonis C.; Berchuck, Andrew; Swerdlow, Anthony; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D.P.; Hall, Per; Easton, Douglas F.; Couch, Fergus J.; Spurdle, Amanda B.; Goldgar, David E.

doi:10.1093/jnci/djv315

Cited by 82 publications

(71 citation statements)

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“…2A). Together these results show that the HDR assay is calibrated relative to levels of cancer risk, with minor functional effects for variants associated with low- or modest risks of breast cancer such as c.9976A>T, p.Lys3326Ter (K3326X) (OR=1.28) (27) and K2729N (OR=1.41), more substantial functional effects for the intermediate risk Y3035S (OR=2.52), and strong effects for known pathogenic variants such as D2723H and R3052W (Fig. 2A).…”

Section: Resultsmentioning

confidence: 76%

“…The variant was predicted neutral by a protein likelihood prediction model (31), but was predicted deleterious by other in silico prediction models including MetaLR, MetaSVM, Vest3, and A-GVGD (prior probability of pathogenicity of 0.66) (Supplementary Table S2). However, the HDR V-C8 cell-based assay showed only mildly reduced activity similar to K2729N (OR=1.41) and p.K3326X (OR=1.28) (27), which are both classified as neutral (Fig. 2A).…”

Section: Discussionmentioning

confidence: 99%

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BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

et al. 2017

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Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR=2.52, p=0.04) and BRCA1 c.5096G>A, p.Arg1699Gln (OR=4.29, p=0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR=2.68, p=0.004) and c.8187G>T, p.Lys2729Asn (OR=1.4, p=0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared to wildtype. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants.

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Section: Resultsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

et al. 2017

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“…In addition, 6 men harbored the BRCA2 K3326⋆ polymorphism, a C-terminal truncating variant that is unlikely to be associated with a predisposition to prostate cancer. 30 It should be noted that to accommodate Cancer Genome Atlas requirements, the majority of tumors had high-risk characteristics: 90% were clinical stage T2c or greater, and 91% of the carcinomas had a Gleason score higher than 6, which far exceeds the approximately 30% of cancers with a Gleason score higher than 6 that was reported among men whose cancer was diagnosed by screening. 31–33 Presumed pathogenic mutations in DNA-repair genes were identified in 2 of 45 men (4%) who had cancer with a Gleason score of 6, in 9 of 249 men (4%) who had cancer with a Gleason score of 7, and in 12 of 205 men (6%) who had cancer with a Gleason score of 8, 9, or 10 (P = 0.37 for trend).…”

Section: Resultsmentioning

confidence: 99%

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

et al. 2016

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BACKGROUND Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.)

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“…We also assessed germline sequences and identified one potentially pathogenic variant (rs11571833; K3326*) in a patient with a somatic mutation (Table S5). This variant has previously been associated with risk of breast and ovarian cancer (Meeks et al, 2016). Four missense variants were present in both germline and tumor DNA, of which 3 were predicted to be deleterious; none of these have been reported as pathogenic.…”

Section: Resultsmentioning

confidence: 99%

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

et al. 2017

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SUMMARY Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localised therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors that showed differential risk of recurrence. The higher risk subtype was characterised by loss of 9q including TSC1, increased KI67 labelling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone-lysine demethylase KDM6A were present in non-invasive tumors from females than males.

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BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

Abstract: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

Cited by 82 publications

References 50 publications

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency

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