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Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma

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ABSTRACT

The presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.

Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).

Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.

Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.

Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.

No MeSH data available.


Hematoxylin and eosin stained images of ADC (A), SCC (B), and PM (C) (Original magnification 40x). Immunohistochemistry of PM reported a positive staining for Calretinin (D), CK-7 (E), and CK5&6 (F), whereas a negative staining for TFF-1 (G) and p63 (H) (Original magnification 40x).
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Figure 2: Hematoxylin and eosin stained images of ADC (A), SCC (B), and PM (C) (Original magnification 40x). Immunohistochemistry of PM reported a positive staining for Calretinin (D), CK-7 (E), and CK5&6 (F), whereas a negative staining for TFF-1 (G) and p63 (H) (Original magnification 40x).

Mentions: We describe the case of a Caucasian male patient with a medical history of heavy smoking habit (100 pack-years), chronic obstructive pulmonary disease (COPD), and no exposure to asbestos. Before being referred to our unit, the patient was initially followed and treated in a different institution; hence, part of the patient's oncologic history was retrospectively retraced when he came to our attention (Fig. 1). In January 2009, the patient, aged 73 years, was subjected to a chest X-ray as preoperative examination for minor surgery with the incidental detection of a suspicious opacity in the left lower lobe. The subsequent diagnostic work-up confirmed a high-risk lesion in the left lower lobe; in addition, the computed tomography (CT) scan identified a smaller lesion in the right upper lobe (22 mm), which was considered an indeterminate lung nodule due to its morphologic characteristics, along with unspecific micro-nodules in the same lung. As the position of the pulmonary findings and the structural lung alterations caused by COPD prevented the collection of bioptic samples, the decision of approaching the left lung lesion with surgery and periodically evaluate the evolution of the indeterminate nodule was taken. Hence, the patient underwent left lung lower lobe segmental resection in April 2009, with postoperative diagnosis of stage IB lung adenocarcinoma (ADC) with solid and glandular patterns and foci of mucus secretion (Fig. 2A). The immunohistochemistry (IHC) analysis revealed positivity for TTF-1, consistently with the diagnosis of a lung primary tumor. The postoperative pathological staging was pT2a, G3, Nx, Mx.


Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma
Hematoxylin and eosin stained images of ADC (A), SCC (B), and PM (C) (Original magnification 40x). Immunohistochemistry of PM reported a positive staining for Calretinin (D), CK-7 (E), and CK5&6 (F), whereas a negative staining for TFF-1 (G) and p63 (H) (Original magnification 40x).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5134773&req=5

Figure 2: Hematoxylin and eosin stained images of ADC (A), SCC (B), and PM (C) (Original magnification 40x). Immunohistochemistry of PM reported a positive staining for Calretinin (D), CK-7 (E), and CK5&6 (F), whereas a negative staining for TFF-1 (G) and p63 (H) (Original magnification 40x).
Mentions: We describe the case of a Caucasian male patient with a medical history of heavy smoking habit (100 pack-years), chronic obstructive pulmonary disease (COPD), and no exposure to asbestos. Before being referred to our unit, the patient was initially followed and treated in a different institution; hence, part of the patient's oncologic history was retrospectively retraced when he came to our attention (Fig. 1). In January 2009, the patient, aged 73 years, was subjected to a chest X-ray as preoperative examination for minor surgery with the incidental detection of a suspicious opacity in the left lower lobe. The subsequent diagnostic work-up confirmed a high-risk lesion in the left lower lobe; in addition, the computed tomography (CT) scan identified a smaller lesion in the right upper lobe (22 mm), which was considered an indeterminate lung nodule due to its morphologic characteristics, along with unspecific micro-nodules in the same lung. As the position of the pulmonary findings and the structural lung alterations caused by COPD prevented the collection of bioptic samples, the decision of approaching the left lung lesion with surgery and periodically evaluate the evolution of the indeterminate nodule was taken. Hence, the patient underwent left lung lower lobe segmental resection in April 2009, with postoperative diagnosis of stage IB lung adenocarcinoma (ADC) with solid and glandular patterns and foci of mucus secretion (Fig. 2A). The immunohistochemistry (IHC) analysis revealed positivity for TTF-1, consistently with the diagnosis of a lung primary tumor. The postoperative pathological staging was pT2a, G3, Nx, Mx.

View Article: PubMed Central - PubMed

ABSTRACT

The presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.

Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).

Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.

Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.

Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.

No MeSH data available.