Loss of heterozygosity on chromosome arm 11q in lung carcinoids

doi:10.1053/hupa.2001.22762

Human Pathology

Volume 32, Issue 3, March 2001, Pages 333-338

https://doi.org/10.1053/hupa.2001.22762 Get rights and content

Abstract

Neuroendocrine lung tumors such as typical carcinoid, atypical carcinoid, small-cell lung carcinoma, and large-cell neuroendocrine carcinoma represent a variable group with different biologic characteristics and unclear genetical relationships. We investigated the pattern of allelic loss on chromosome arm 11q in 20 sporadic carcinoid tumors of the lung using 10 microsatellite markers. Loss of heterozygosity was found in 13 of 20 tumors. In 5 of 9 typical carcinoids, 3 distinct regions of allelic loss were identified: 11q13.1 (D11S1883), 11q14.3-11q21 (D11S906), and 11q25 (D11S910). Atypical carcinoids showed loss of heterozygosity at 4 different regions: the first, most proximal region at 11q13 between markers PYGM and D11S937; the second at 11q14.3-11q21 (D11S906); and the third and fourth defined by markers D11S939 (11q23.2-23.3) and D11S910 (11q25). However, the region 11q13 harboring the MEN1 gene was more frequently affected in atypical carcinoids (7 of 11) than in typical carcinoids (2 of 9). The high rate of allelic losses within chromosomal region 11q13 in atypical carcinoids emphasizes the importance of this region for tumor developement. We also recognized that more aggressive atypical carcinoids defined by high mitotic counts, vascular invasion, and/or organ metastasis are combined with increased allelic losses. HUM PATHOL 32:333-338. Copyright © 2001 by W.B. Saunders Company

Section snippets

Materials and methods

We selected 9 TCs and 11 ATCs from our pulmonary pathology archive. In all these cases, formalin-fixed and paraffin-embedded tumor tissue and normal tissue were available. Our TCs and ATCs were re-evaluated using the criteria of the new World Health Organization classification.¹ All relevant data are given to enable comparison with other studies (Table 1).The area of the high-power field was calculated as proposed by Travis et al,¹⁶ and the number of mitoses was corrected for 2 mm².

Results

LOH was observed in 7 of the 10 loci. Thirteen of the 20 lung carcinoids showed LOH in at least 1 locus on chromosome arm 11q. With respect to the tumor entities, the following was found.

Discussion

There are a few reports of mutations occuring within chromosome 11q in sporadic lung carcinoids.6, 8, 20 Supported by CGH data9, 21 (also Ullmann R, et al, unpublished observations) it turns out that DNA losses on chromosome 11q represent a characteristic cytogenetic alteration of lung carcinoids. Our findings show that an allelic loss within 11q13 is more frequent in ATCs (7 of 11) than in TCs (2 of 9; P <.064). However, conflicting results have been published (Table 5).

. Summary of Genetic Data

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Molecular Classification of Neuroendocrine Tumors of the Thymus
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For example, AC and LCNEC are the most frequent subtypes in the thymus, whereas TC and SCC prevail in the lung. Furthermore, the correlation between genotype and phenotype in patients with menin 1 (MEN1) is reported to be lower in TNET, and the genetic profile of thymic carcinoids differs from pulmonary carcinoids.10-16 On the other hand, the current WHO classification has shown clinical relevance and reflects genetic alterations found in TNET.16
The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems.
One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features.
Whole-genome sequencing data fell into three clusters: CNI_low, CNI_int, and CNI_high. CNI_low and CNI_int comprised not only TC and AC, but also six LCNECs. CNI_high contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2).
TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication.
Protein phosphatase 2A A regulates A protein expression and stability
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These studies have revealed that although the Aα isoform is altered in 35% of human cancers, homozygous deletions of Aα are exceedingly rare, occurring in only 0.3% of patient tumors (Fig. S2, A and B). In contrast, deletions of Aβ are more common, as the Aβ gene PPP2R1B is located within the chromosomal region 11q23, a region commonly deleted in cancer (9–13). To define the molecular basis for why homozygous Aα deletion appears to be unfavorable for cancer cell growth, we used a combination of biochemical and cellular assays to examine the functional ramifications of complete loss of the Aα subunit.
Protein phosphatase 2A (PP2A) represses many oncogenic signaling pathways and is an important tumor suppressor. PP2A comprises three distinct subunits and forms through a highly regulated biogenesis process, with the scaffolding A subunit existing as two highly related isoforms, Aα and Aβ. PP2A's tumor-suppressive functions have been intensely studied, and PP2A inactivation has been shown to be a prerequisite for tumor formation. Interestingly, although partial loss of the Aα isoform is growth promoting, complete Aα loss has no transformative properties. Additionally, in cancer patients, Aα is found to be inactivated in a haploinsufficient manner. Using both cellular and in vivo systems, colorectal and endometrial cancer cell lines, and biochemical and cellular assays, here we examined why the complete loss of Aα does not promote tumorigenesis. CRISPR/Cas9-mediated homozygous Aα deletion resulted in decreased colony formation and tumor growth across multiple cell lines. Protein expression analysis of PP2A family members revealed that the Aα deletion markedly up-regulates Aβ protein expression by increasing Aβ protein stability. Aβ knockdown in control and Aα knockout cell lines indicated that Aβ is necessary for cell survival in the Aα knockout cells. In the setting of Aα deficiency, co-immunoprecipitation analysis revealed increased binding of specific PP2A regulatory subunits to Aβ, and knockdown of these regulatory subunits restored colony-forming ability. Taken together, our results uncover a mechanism by which PP2A Aα regulates Aβ protein stability and activity and suggests why homozygous loss of Aα is rarely seen in cancer patients.
Neuroendocrine Tumors of the Lung Other Than Small Cell Lung Cancer
2018, IASLC Thoracic Oncology
Deletions of 11q22.3-q25 are associated with atypical lung carcinoids and poor clinical outcome
2011, American Journal of Pathology
Citation Excerpt :
Together, these observations imply that other mechanisms of tumorigenesis exist in pulmonary carcinoids not associated with MEN1 gene aberrations, including involvement of candidate genes in the 11q22.3-q25 region. Conflicting results have been published on the frequency of 11q loss in lung carcinoids in conventional CGH or loss of heterozygosity studies.13,14,16,29,30 Frequency ranged from 0% to 56% (mean, 34%) in TCs, and from 10% to 73% (mean, 50%) in ACs.
Carcinoids are slow-growing neuroendocrine tumors that, in the lung, can be subclassified as typical (TC) or atypical (AC). To identify genetic alterations that improve the prediction of prognosis, we investigated 34 carcinoid tumors of the lung (18 TCs, 15 ACs, and 1 unclassified) by using array comparative genomic hybridization (array CGH) on 3700 genomic bacterial artificial chromosome arrays (resolution ≤1 Mb). When comparing ACs with TCs, the data revealed: i) a significant difference in the average number of chromosome arms altered (9.6 versus 4.2, respectively; P = 0.036), with one subgroup of five ACs having more than 15 chromosome arms altered; ii) chromosomal changes in 30% of ACs or more with additions at 9q (≥1 Mb) and losses at 1p, 2q, 10q, and 11q; and iii) 11q deletions in 8 of 15 ACs versus 1 of 18 TCs (P = 0.004), which was confirmed via fluorescence in situ hybridization. The four critical regions of interest in 45% ACs or more comprised 11q14.1, 11q22.1-q22.3, 11q22.3-q23.2, and 11q24.2-q25, all telomeric of MEN1 at 11q13. Results were correlated with patient clinical data and long-term follow-up. Thus, there is a strong association of 11q22.3-q25 loss with poorer prognosis, alone or in combination with absence of 9q34.11 alterations (P = 0.0022 and P = 0.00026, respectively).
Rare Tumors of Childhood
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Well-Differentiated Neuroendocrine Carcinomas: The Spectrum of Histologic Subtypes and Various Clinical Behaviors
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Deletions of 11q DNA material (including the MEN1 gene locus) were frequent in the former tumors, whereas these aberrations were rare in the latter tumors. Furthermore, losses of 10q and 13q sequences were common in WDNC and served to differentiate them from TC.56-58 Gene sequence analysis of Ki-ras-2 and c-raf-1 has failed to show any evidence of point mutation among pulmonary neuroendocrine tumors.43,48,59
The term “well-differentiated neuroendocrine carcinoma” was coined to describe a variety of demonstrably neuroendocrine tumors which were more aggressive (both with respect to their histologic appearance and their clinical course) than (typical) bronchial carcinoids but were also clearly distinguishable from small cell neuroendocrine carcinomas. This umbrella term encompasses a variety of tumors previously described by a variety of terms including “atypical” carcinoids, “malignant tumorlets,” peripheral stage I small-cell carcinoma, as well as neoplasms described simply as “undifferentiated carcinoma” (prior to the recognition of their neuroendocrine properties). As such, this term is a broad term and is not simply synonymous with “atypical carcinoid.” Over time, at least 3 subtypes have been identified based upon their histologic appearance and mitotic index, with correspondingly aggressive clinical courses.

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^*: Supported by the Jubilee Fund of the Austrian National Bank, Project 6914, which is gratefully acknowledged. R.U. was supported by the Styrian Cancer Society.

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Original ContributionsLoss of heterozygosity on chromosome arm 11q in lung carcinoids*

Abstract

Section snippets

Materials and methods

Results

Discussion

J Thorac Cardiovasc Surg

Hum Pathol

Cancer Genet Cytogenet

Am J Pathol

Am J Pathol

Hum Pathol

Hum Pathol

Hum Pathol

Cell

Biochim Biophys Acta

Am J Pathol

Histological typing of lung and pleural tumors

Morphological and immunohistochemical study of typical and atypical carcinoids of the lung with clinico-pathological correlation

Endocr Rel Cancer

Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11

N Engl J Med

Carcinoid tumors frequently display genetic abnormalities involving chromosome 11

J Clin Endocrinol Metab

Original Contributions
Loss of heterozygosity on chromosome arm 11q in lung carcinoids*