Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer

Simona Coco, Silvia Bonfiglio, Davide Cittaro, Irene Vanni, Marco Mora, Carlo Genova, Maria Giovanna Dal Bello, Simona Boccardo, Angela Alama, Erika Rijavec, Claudio Sini, Valeria Rossella, Giulia Barletta, Federica Biello, Anna Truini, Cristina Bruzzo, Maurizio Gallo, Dejan Lazarevic, Alberto Ballestrero, Francesco Grossi

Research output: Contribution to journalArticle

Abstract

Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

Original languageEnglish
JournalCancers
Volume11
Issue number4
DOIs
Publication statusPublished - Mar 28 2019

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Exome
Lung Neoplasms
Breast Neoplasms
Smoking
Survivors
Neoplasms
Population
Genetic Predisposition to Disease
Genes
Habits

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Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer. / Coco, Simona; Bonfiglio, Silvia; Cittaro, Davide; Vanni, Irene; Mora, Marco; Genova, Carlo; Dal Bello, Maria Giovanna; Boccardo, Simona; Alama, Angela; Rijavec, Erika; Sini, Claudio; Rossella, Valeria; Barletta, Giulia; Biello, Federica; Truini, Anna; Bruzzo, Cristina; Gallo, Maurizio; Lazarevic, Dejan; Ballestrero, Alberto; Grossi, Francesco.

In: Cancers, Vol. 11, No. 4, 28.03.2019.

Research output: Contribution to journalArticle

Coco, S, Bonfiglio, S, Cittaro, D, Vanni, I, Mora, M, Genova, C, Dal Bello, MG, Boccardo, S, Alama, A, Rijavec, E, Sini, C, Rossella, V, Barletta, G, Biello, F, Truini, A, Bruzzo, C, Gallo, M, Lazarevic, D, Ballestrero, A & Grossi, F 2019, 'Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer', Cancers, vol. 11, no. 4. https://doi.org/10.3390/cancers11040441
Coco, Simona ; Bonfiglio, Silvia ; Cittaro, Davide ; Vanni, Irene ; Mora, Marco ; Genova, Carlo ; Dal Bello, Maria Giovanna ; Boccardo, Simona ; Alama, Angela ; Rijavec, Erika ; Sini, Claudio ; Rossella, Valeria ; Barletta, Giulia ; Biello, Federica ; Truini, Anna ; Bruzzo, Cristina ; Gallo, Maurizio ; Lazarevic, Dejan ; Ballestrero, Alberto ; Grossi, Francesco. / Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer. In: Cancers. 2019 ; Vol. 11, No. 4.
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abstract = "Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.",
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AU - Coco, Simona

AU - Bonfiglio, Silvia

AU - Cittaro, Davide

AU - Vanni, Irene

AU - Mora, Marco

AU - Genova, Carlo

AU - Dal Bello, Maria Giovanna

AU - Boccardo, Simona

AU - Alama, Angela

AU - Rijavec, Erika

AU - Sini, Claudio

AU - Rossella, Valeria

AU - Barletta, Giulia

AU - Biello, Federica

AU - Truini, Anna

AU - Bruzzo, Cristina

AU - Gallo, Maurizio

AU - Lazarevic, Dejan

AU - Ballestrero, Alberto

AU - Grossi, Francesco

PY - 2019/3/28

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N2 - Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

AB - Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

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