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Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma

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Harvard

Johansson, PA, Nathan, V, Bourke, LM, Palmer, JM, Zhang, T, Symmons, J, Howlie, M, Patch, A-M, Read, J, Holland, EA, Schmid, H, Warrier, S, Glasson, W, Höiom, V, Wadt, K, Jönsson, G, Olsson, H, Ingvar, C, Mann, G, Brown, KM, Hayward, NK & Pritchard, AL 2019, 'Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma' Melanoma Research, bind 29, nr. 5, s. 483-490. https://doi.org/10.1097/CMR.0000000000000613

APA

Johansson, P. A., Nathan, V., Bourke, L. M., Palmer, J. M., Zhang, T., Symmons, J., ... Pritchard, A. L. (2019). Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma. Melanoma Research, 29(5), 483-490. https://doi.org/10.1097/CMR.0000000000000613

CBE

Johansson PA, Nathan V, Bourke LM, Palmer JM, Zhang T, Symmons J, Howlie M, Patch A-M, Read J, Holland EA, Schmid H, Warrier S, Glasson W, Höiom V, Wadt K, Jönsson G, Olsson H, Ingvar C, Mann G, Brown KM, Hayward NK, Pritchard AL. 2019. Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma. Melanoma Research. 29(5):483-490. https://doi.org/10.1097/CMR.0000000000000613

MLA

Vancouver

Author

Johansson, Peter A ; Nathan, Vaishnavi ; Bourke, Lauren M ; Palmer, Jane M ; Zhang, Tongwu ; Symmons, Judith ; Howlie, Madeleine ; Patch, Ann-Marie ; Read, Jazlyn ; Holland, Elizabeth A ; Schmid, Helen ; Warrier, Sunil ; Glasson, William ; Höiom, Veronica ; Wadt, Karin ; Jönsson, Göran ; Olsson, Håkan ; Ingvar, Christian ; Mann, Graham ; Brown, Kevin M ; Hayward, Nicholas K ; Pritchard, Antonia L. / Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma. I: Melanoma Research. 2019 ; Bind 29, Nr. 5. s. 483-490.

Bibtex

@article{834d3adcc9fc4d4e8f6f8289a1ea7664,
title = "Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma",
abstract = "Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.",
author = "Johansson, {Peter A} and Vaishnavi Nathan and Bourke, {Lauren M} and Palmer, {Jane M} and Tongwu Zhang and Judith Symmons and Madeleine Howlie and Ann-Marie Patch and Jazlyn Read and Holland, {Elizabeth A} and Helen Schmid and Sunil Warrier and William Glasson and Veronica H{\"o}iom and Karin Wadt and G{\"o}ran J{\"o}nsson and H{\aa}kan Olsson and Christian Ingvar and Graham Mann and Brown, {Kevin M} and Hayward, {Nicholas K} and Pritchard, {Antonia L}",
year = "2019",
month = "10",
doi = "10.1097/CMR.0000000000000613",
language = "English",
volume = "29",
pages = "483--490",
journal = "Melanoma Research",
issn = "0960-8931",
publisher = "Lippincott Williams & Wilkins",
number = "5",

}

RIS

TY - JOUR

T1 - Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma

AU - Johansson, Peter A

AU - Nathan, Vaishnavi

AU - Bourke, Lauren M

AU - Palmer, Jane M

AU - Zhang, Tongwu

AU - Symmons, Judith

AU - Howlie, Madeleine

AU - Patch, Ann-Marie

AU - Read, Jazlyn

AU - Holland, Elizabeth A

AU - Schmid, Helen

AU - Warrier, Sunil

AU - Glasson, William

AU - Höiom, Veronica

AU - Wadt, Karin

AU - Jönsson, Göran

AU - Olsson, Håkan

AU - Ingvar, Christian

AU - Mann, Graham

AU - Brown, Kevin M

AU - Hayward, Nicholas K

AU - Pritchard, Antonia L

PY - 2019/10

Y1 - 2019/10

N2 - Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

AB - Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.

U2 - 10.1097/CMR.0000000000000613

DO - 10.1097/CMR.0000000000000613

M3 - Journal article

VL - 29

SP - 483

EP - 490

JO - Melanoma Research

JF - Melanoma Research

SN - 0960-8931

IS - 5

ER -

ID: 59279809