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. 2020 Sep 15;26(1):e78–e89. doi: 10.1634/theoncologist.2020-0509

Cyclin Pathway Genomic Alterations Across 190,247 Solid Tumors: Leveraging Large‐Scale Data to Inform Therapeutic Directions

Denis L Jardim 1,†,✉, Sherri Z Millis 2,†, Jeffrey S Ross 2, Michelle Sue‐Ann Woo 2, Siraj M Ali 2, Razelle Kurzrock 3,✉
PMCID: PMC7794175  PMID: 32885893

Abstract

Background

We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.

Methods

Using comprehensive genomic profiling (315 genes, >500× coverage), samples were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), hormone genes (estrogen receptor 1 [ESR1], androgen receptor [AR]), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1).

Results

Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio [OR], 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations).

Conclusion

Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers.

Implications for Practice

Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.

Keywords: Cell cycle, CDK4, CDK6, Precision oncology, Molecular genetics, Cancer genome, Targeted therapy

Short abstract

This article identifies molecular alterations in genes involved in the cyclin activation/sensitizing pathways and reports coexisting resistance and hormone pathway alterations in 190,247 diverse solid tumors that underwent next‐generation sequencing.

Introduction

Proliferation of normal cells is tightly controlled during the cell cycle. Cyclin‐dependent kinases (CDKs), upon ligation to cyclin proteins, play a major role in these processes. At the transition of G1 to S phase of mitosis, cyclin D interacts with CDK4 and CDK6, and cyclin E interacts with CDK2 to form complexes that phosphorylate and inactivate retinoblastoma proteins (Rb) [1]. Phosphorylated Rb1 releases the early region 2 binding factor (E2F), which constitutes a complex family of transcriptional regulators that ultimately promote cell proliferation (Fig. 1) [2]. Other cyclins, including cyclins A and B and their associated CDKs, also exert regulatory functions during the subsequent steps of cell cycle regulation [3].

Figure 1.

Figure 1

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Genomic alterations in the cyclin pathway in patients with cancer. Schematic representation of genes that are part of the cyclin pathway, including their relationship with the mitotic cycle and transition from G1 to S phase. Genes that are shaded in light gray may suffer genomic alterations that can lead to cyclin pathway upregulation. Alterations in genes that could lead to resistance to cyclin inhibitors (supplemental online Table 1) are shaded in red. Numbers in brackets are the frequencies of genomic alterations in each gene detected in the current study in the overall population of 190,247 solid tumors. Dotted arrows reflect inhibition of target.

In cancer cells, the CDK‐Rb‐E2F axis is frequently deregulated, leading to uncontrolled cell division and progression. Alterations in cyclins and their CDKs, as well as inactivating mutations in RB1, could lead to increased E2F activity and higher S‐phase fraction in tumor cells [4]. Various factors are responsible for upregulation of this axis, including CCND gene amplification [5], cyclin D overexpression [6], CDK4/6 mutation/amplification [7], and loss of negative regulators of the complex, such as CDKN2A and CDKN2B [8]. Breast cancer is an example of a tumor that presents with deregulation of the cyclin pathway. Multiple studies suggest that, in hormone receptor–positive (HR+) breast cancer, cyclin pathway activation may lead to resistance to traditional endocrine therapy [9]. Indeed, inhibitors of CDK4/6 were clinically tested in patients with HR+ breast cancer and led to consistent benefit when administered with aromatase inhibitors [10, 11, 12]. Palbociclib, ribociclib, and abemaciclib are now U.S. Food and Drug Administration–approved CDK4/6 inhibitors for advanced breast cancer [13].

Despite the recent success of CDK inhibitors in breast cancer, biomarkers are lacking that help identify which patients are likely to derive benefit from these treatments. In addition, primary and acquired resistance to CDK inhibitors can be mediated by genomic alterations in genes involved in this pathway, such as RB1 and CCNE1 [14]. Both genes can be classified as potential resistance alterations related to CDK inhibition. Using biomarker knowledge for development and approval of targeted therapies is associated with higher therapeutic success [15, 16]. As previously demonstrated, many solid tumors harbor genetic alterations in cyclin pathway genes, including CCN amplifications and CDKN2A and CDK4/6 aberrations [5, 17, 18, 19]. Cyclin inhibitors are in development for a variety of solid tumors with the strategy of selecting patients based on genomic characterization of the pathway [20, 21]. Hence, comprehensive characterization of the cyclin pathway alterations in the pancancer setting is needed.

Herein, we identified molecular alterations in genes involved in the cyclin activation/sensitizing pathway, as well as coexisting resistance and hormone pathway alterations, in 190,247 diverse solid tumors that underwent next‐generation sequencing (NGS) in a Clinical Laboratory Improvement Amendment (CLIA)–certified laboratory.

Materials and Methods

Tissue Sampling

Consecutive samples submitted by thousands of physicians worldwide were analyzed using a CLIA‐certified laboratory (Foundation Medicine, https://www.foundationmedicine.com). Tissue diagnoses were designated according to the pathology report and further verified by a pathologist at Foundation Medicine. DNA was extracted from formalin‐fixed, paraffin‐embedded tissue, as previously described [22]. Patient identification was redacted for the study. Approval for the Foundation Medicine cohort, including a waiver of informed consent and Health Insurance Portability and Accountability Act waiver of authorization, was obtained from the Western Institutional Review Board (protocol no. 20152817).

Next‐Generation Sequencing

DNA was extracted from formalin‐fixed, paraffin‐embedded sections, and comprehensive genomic profiling was performed on hybridization‐captured, adaptor ligation‐based libraries to a median depth of coverage of >500× [22]. The platform simultaneously sequenced the coding regions of 315 cancer‐related genes plus introns from 28 genes often rearranged or altered in cancer. Alterations captured by NGS included base pair substitutions, insertions/deletions (both short and long), copy number alterations, and rearrangements.

Clustering of Genomic Alterations and Tumor Types

Genomic alterations of interest were classified either as activators of the cyclin pathway (eight genes, including CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], and SMARCB1) or as related to potential resistance pathways related to CDK4/6 inhibition (RB1 and CCNE1). Additionally, genomic alterations in pathways related to cyclins (crosstalk pathways or targetable with drugs developed in combination with cyclin inhibitors, including SMAD3, CDKN1A, CDKN1B, CDKN1C, estrogen w?>receptor 1 [ESR1], and androgen receptor [AR]) were analyzed (supplemental online Table 1). Analysis of frequencies were performed by disease ontologies clustered according to American Joint Committee on Cancer 8th edition [23] and consistent with the tumor histologies on the submitted pathology report.

Statistical Analysis

Statistical analysis was performed using GraphPad Prism, Python 2.7, and Anaconda version 4‐4.3.21 (Anaconda, Austin, TX). Co‐occurrence analysis was performing matching cyclin pathway genomic alterations with three different subsets of genomic alterations (resistance pathway, cyclin‐related, and ESR1/AR).

Results

Alterations in any cyclin pathway activating/sensitizing genes (supplemental online Table 1) were found in 24% of the 190,247 tumors analyzed (Fig. 1). The most frequent alterations were CDKN2A loss (13.9%), CDKN2B loss (12.5%), and CCND1 amplification (4.8%). CDK4 and CDK6 alterations were detected in 3% and 1.5% of samples, respectively. Overall, 89% of cases presented a single genomic alteration in one of the eight activating/sensitizing genes selected as part of the cyclin pathway (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1). Alterations in two cyclin pathway activating/sensitizing genes occurred in 20% cases, and 1% of cases had more than two co‐occurring alterations. The frequency of cyclin pathway activating/sensitizing alterations varied by histology and tumor type (Fig. 2A and C).

Figure 2.

Figure 2

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Cyclin pathway gene alterations in patients with cancer. Percent of patients with alterations is shown on the y‐axis. Analysis of alteration frequency (%) is calculated as harboring at least one alteration per case. Numbers in brackets represent numbers of patients. (A): Analysis of overall alterations by histopathology. “All” represents all samples, regardless of histology (Fig. 3A). (B): Specific gene alteration frequencies by histopathology (Fig. 3A). (C): Analysis of overall alterations by disease type (Fig. 3B). (D): Specific gene alteration by disease type. Other includes parathyroid carcinoma, placenta choriocarcinoma, spine ependymoma, soft tissue paraganglioma, spine glioma, eye tumors, heart tumors, neuroblastoma, mediastinal neoplasias, pineal tumor, schwannoma, spleen sarcoma, scrotum tumors, and tracheal carcinomas (Fig. 3B). Abbreviations: GIST, gastrointestinal stromal tumor; NSCLC, non‐small cell lung cancer; SCLC, small cell lung cancer.

Characteristics of Cyclin Gene Alterations

Different types of alterations were identified in the eight cyclin pathway activating/sensitizing genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1) (supplemental online Table 2). Copy number changes were the sole type of alteration detected in CDK4, CDK6, and CCND1 genes (all amplifications). CDKN2A was uniformly affected by gene loss, whereas 1% of CDKN2B alterations were rearrangements. In fact, seven of the eight cyclin genes presented mostly (or exclusively) with copy number changes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss]). A single nucleotide change was the predominant SMARCB1 alteration (73% of cases of altered SMARCB1). SMARCB1 was the most frequently rearranged gene of the pathway (7% of altered SMARCB1). Of the other genes included in this analysis, RB1 (67% of cases altered RB1), ESR1 (79%), CDKN1A (95%), and CDKN1B (82%) presented more frequently with single nucleotide changes. CDKN2C and AR presented more frequently with copy number changes (54% and 59% of cases with alterations, respectively).

Cyclin Activating/Sensitizing (CDK4 Amplification, CDK6 Amplification, CCND1, CCND2, CCND3, CDKN2B [Loss], CDKN2A [Loss], SMARCB1) Alterations by Histology

All 17 histologies demonstrated cyclin activating/sensitizing pathway alteration in all genes included as part of the pathway (except for the absence of CCND3 alterations in gastrointestinal stromal tumors) (Fig. 2A, B and Fig. 3A).

Figure 3.

Figure 3

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Chart of alterations (%) in cyclin pathway genes. The percentages of patients with an alteration are shown. (A): Alterations are categorized by histopathologic subtype (this chart corresponds to Fig. 2A and B). (B): Alterations are categorized by disease type (this chart corresponds to Fig. 2C and D). On both panels, pink denotes percentage of patients with alteration above median and yellow denotes percentage below median; those without color are 0%; colored yellow 0% are between 0.001% and 0.5%. Abbreviations: amp, amplification; del, deletion; GIST, gastrointestinal stromal tumor; NSCLC, non‐small cell lung cancer.

Significant variability was seen in the patterns of cyclin activating/sensitizing alterations between different disease ontologies. Gliomas (54% of tumors had cyclin activating/sensitizing pathway alterations) and urothelial carcinoma (41%) were the histologies that most frequently harbored alterations; adenoid cystic (7%) and small cell carcinoma (6%) were the least commonly altered. Neuroendocrine carcinoma (which is in the same nosologic spectrum as small cell carcinoma) was also among the tumor histologies with a lower frequency of cyclin activating/sensitizing alterations (12%).

CDKN2A and CDKN2B deletions were the most frequent cyclin activating/sensitizing alterations across histologies, with similar frequencies between both genes in each histology (Fig. 3A). Although gliomas are associated with high frequencies of cyclin activating/sensitizing alterations, CCND1 (0.3% of cases of gliomas), CCND3 (0.2%), and SMARCB1 (0.7%) were rarely altered in gliomas compared with other histologies. Alteration frequencies of note by histology include a high frequency of CCND1 amplification in urothelial carcinoma (12.3%) and squamous cell carcinoma (13%), a high frequency of CDK4 alterations in sarcomas (10.4%), and a relatively high proportion of CCND2 alterations in germ cell tumors (16.3%, compared with 1.5% in the overall population).

Cyclin Activating/Sensitizing (CDK4 Amplification, CDK6 Amplification, CCND1, CCND2, CCND3, CDKN2B [Loss], CDKN2A [Loss], SMARCB1) Alterations by Disease Type

The top five of the 33 disease types analyzed harboring any type of cyclin activating/sensitizing alterations were brain (47.1% of cases of brain tumors had a cyclin alteration), esophageal (40.3%), mesothelioma (37.9%), bladder (37.9%), and primary bone cancers (35.7%) (Fig. 2C, D and Fig. 3B). Except for CDK4 in thymic cancer and CCND3 and SMARCB1 in penile cancer, all other genes were altered in at least one case in each disease type. Cyclin gene alterations were less frequently detected in cervical (5.2%), colorectal (7.8%), uterine (8.3%), and prostate (9.7%) cancers.

Comparing the overall frequency of each gene with the specific disease types, some alterations were typical in some tumors (Fig. 2C, D and Fig. 3B). Breast cancer was the leading tumor for CCND1 amplification (17.3% of cases vs. 4.8% overall for all tumors), soft tissue sarcomas for CDK4 alterations (12% vs. 3% overall), esophageal cancer for CDK6 alterations (8.6% vs. 1.5% overall), testicular cancers typically presented CCND2 alterations (23.4% vs. 1.5% overall), bone tumors a high frequency of CCND3 alterations (6.2% vs. 1.4% overall), and, finally, kidney cancers a relevant frequency of SMARCB1 alterations (3% vs. 0.7% overall).

We discerned interesting information in uncommon tumors (supplemental online Table 3). Bladder (41%) and esophageal (45.5%) squamous cell carcinomas and malignant peripheral nerve sheath tumors (46.4%) harbored CDKN2A alterations. Breast neuroendocrine carcinoma presented a high frequency of CCND1 amplification (26.3%). Overall, 38.1% of heart sarcomas had CDK4 alterations, and 14.1% had CCND3 alterations. Finally, although SMARCB1 alterations are rare in the overall population (0.7%), some rare tumors presented high frequencies of alterations in this gene, including brain rhabdoid tumor (88.4%), kidney rhabdoid tumor (90%), kidney medullary carcinoma (41.3%), epithelioid sarcoma (56%), and extrarenal rhabdoid tumor (63.6%).

Analysis of Potential Cyclin Pathway Resistance Genes (RB1 and CCNE1)

We analyzed genomic alterations in RB1 and CCNE1 because they may promote resistance to cyclin inhibitors. Overall, RB1 alterations were detected in 7.2% of samples; CCNE1, in 3.6% (supplemental online Figs. 1 and 2). In only 3% of cases were these alterations present simultaneously. Tumors presenting a high frequency of RB1 alterations included bladder cancer (20.9%), nonmelanoma skin cancer (17.9%), soft tissue sarcomas (14.6%), and bone tumors (11.8%). In the case of CCNE1, alterations were frequent in ovarian (12.7%), esophageal (10.3%), and uterine cancers (9%). Although some disease types presented low frequencies of alterations of RB1 and CCNE1, all had alterations.

We also analyzed the likelihood of co‐occurrence of an alteration in the cyclin activation/sensitizing pathway and in a possible resistance pathway (RB1 and CCNE1) by disease type (Fig. 4A and Table 1). In three diseases, we identified a higher likelihood of a co‐occurrence of alterations in both pathways compared with an isolated alteration: colorectal cancers (odd ratio [OR], 1.53; p < .001), cervical cancer (OR, 1.29; p < .001), and small intestine (OR, 1.28; p < .001). In all other diseases analyzed, we detected lower likelihood of co‐occurrence compared with an isolated alteration in cyclin activating/sensitizing and resistance pathway.

Figure 4.

Figure 4

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Co‐alteration analysis. (A): Resistance pathway (RB1 and CCNE1) and cyclin pathway co‐incidence. The ratio of alterations in the cyclin pathway only, the resistance pathway only, or alterations in both the cyclin and resistance pathways is shown for all disease types with a significant association between the two pathways (p value ≤.05 for co‐incidence; 33 disease types total had a significant association—Table 1). (B): Related genes (SMAD3, CDKN1A, CDKN1B, CDKN2C) and cyclin pathway co‐incidence. The ratio of alterations in the cyclin pathway only, the related pathway only, or alterations in both the cyclin and related pathways is shown for all disease types with a significant association between the two pathways (p value ≤.05 for co‐incidence; 33 disease types total had a significant association—Table 2). (C): Hormone receptor genes (estrogen receptor 1 [ESR1], androgen receptor [AR]) and cyclin pathway co‐incidence. The ratio of alterations in the cyclin pathway only, the hormone receptor only, or alterations in both the cyclin and hormone pathways is shown for disease types in which prevalence of AR or ESR1 alterations were at least 1%—supplemental online Table 3). Abbreviations: HR, hormone receptor; NSCLC, non‐small cell lung cancer.

Table 1.

Co‐occurrence of alterations in cyclin activating/sensitizing (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], and SMARCB1) and resistance genes (RB1 and CCNE1) in the cyclin pathway

Tumor type Sensitizing alterations only Resistant alterations only Both sensitizing and resistant Neither alteration OR sensitizing alteration in resistant patients a OR resistant alteration in sensitizing patients b p value c
All 43,269 19,934 2,195 124,849 0.39 0.35 .0001
Adrenal gland 92 49 3 496 0.37 0.35 .0001
Ampulla of Vater 69 11 1 141 0.25 0.20 .0001
Anus 87 27 4 552 0.95 0.94 .0001
Bile ducts 1,453 284 67 3,271 0.62 0.55 .0001
Bladder, urothelial tract 1,164 753 77 1,282 0.19 0.17 .0001
Bone 374 164 23 552 0.30 0.25 .0001
Brain 4,442 575 91 4,523 0.28 0.18 .0001
Breast 5,100 2,065 323 12,057 0.46 0.41 .0001
Cervix 68 100 7 1,278 1.29 1.29 .0001
Colon and rectum 1,641 480 62 19,667 1.49 1.53 .0001
Corpus uteri 464 1,282 90 4,823 0.75 0.77 .0001
Esophagus, esophagogastric 1,723 494 95 2,203 0.37 0.29 .0001
Head and neck 1,071 157 30 2,506 0.54 0.46 .0001
Kidney 864 95 14 2,601 0.52 0.45 .0001
Liver 163 110 7 1,077 0.46 0.44 .0001
Lung, NSCLC 10,064 4,642 582 24,365 0.38 0.34 .0001
Melanoma 698 72 7 1,450 0.27 0.21 .0001
Mesothelioma 378 21 5 600 0.50 0.39 .0001
Other 85 13 2 801 1.39 1.44 .0001
Ovary/peritoneal Cancer 1,117 1,785 221 8,542 0.95 0.96 .0001
Pancreas 3,104 453 74 6,784 0.45 0.37 .0001
Penis 34 5 0 96 0.00 0.00 .0463
Prostate 494 551 26 4,285 0.44 0.44 .0001
Salivary glands 312 63 9 950 0.51 0.45 .0001
Skin (nonmelanoma) 201 229 19 919 0.43 0.43 .0001
Small intestine 321 82 16 2,125 1.24 1.28 .0001
Soft tissue sarcoma 1,983 1,089 79 4,055 0.21 0.18 .0001
Stomach 753 206 41 2,461 0.71 0.67 .0001
Testis 73 8 2 139 0.58 0.49 .0001
Thymus 98 11 0 226 0.00 0.00 .0089
Thyroid 172 63 4 1,472 0.57 0.55 .0001
Unknown primary 4,500 1,779 213 10,405 0.35 0.31 .0001
Vagina/vulva 106 21 1 341 0.19 0.16 .0001
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Only tumors with a statistically significant association are shown in this table.

a

Odds ratio of a sensitizing cyclin gene alteration in patients with a resistant cyclin alteration compared with patients with only wild type for resistant cyclin genes.

b

Odds ratio of a resistance cyclin alteration in patients with a sensitizing cyclin alteration compared with patients with only wild type for sensitizing cyclin genes.

c

p value for co‐occurrence test.

Abbreviations: NSCLC, non‐small cell lung cancer; OR, odds ratio.

Co‐Occurrence of Cyclin Activating/Sensitizing (CDK4 Amplification, CDK6 Amplification, CCND1, CCND2, CCND3, CDKN2B [Loss], CDKN2A [Loss], SMARCB1) Alterations and Related Pathway (SMAD3, CDKN1A, CDKN1B, CDKN2C) or Hormone Receptor Alterations

We analyzed the frequency of genes related to cyclin pathway (Fig. 1), including SMAD3, CDKN1A, CDKN1B, and CDKN2C. Overall, any of these genes were altered in 1% of cases (supplemental online Fig. 3). In comparison with other histologies, a higher frequency of CDKN1A alterations was found in urothelial carcinomas (3.5%), CDKN1B in neuroendocrine cancers (3.1%), and CDKN2C in gliomas (2.5%). SMAD3 was rarely altered, regardless of the histology (supplemental online Fig. 4A). As for disease type, a notable finding was a high frequency of alterations in these genes in tumors from the ampulla of Vater compared with other sites (46% vs. 1%); relevant genes altered in this site were CDKN1B (20.7%) and CDKN2C (21.6%). For all tumors, there is a slightly higher likelihood of co‐occurrence between alterations in cyclin‐related genes (SMAD3, CDKN1A, CDKN1B, CDKN2C) and activating/sensitizing genes of the cyclin pathway (OR, 1.11; p < .001) (vs. an alteration in a cyclin‐related gene in the presence of wild‐type activating/sensitizing cyclin genes) (Fig. 4B and Table 2); however, substantial variation appeared when individual tumor types were analyzed. Tumors with a higher likelihood of co‐occurrence included primary bone (OR, 3.61; p < .001) and brain cancers (OR, 3.00; p < .001), whereas a higher likelihood of an isolated alteration was detected in breast (OR, 0.48; p < .001) and prostate tumors (OR, 0.51; p < .001).

Table 2.

Co‐occurrence of alterations in the cyclin activating/sensitizing genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], and SMARCB1) and related genes (SMAD3, CDKN1A, CDKN1B, CDKN2C)

Tumor type Sensitizing alterations only Related alterations only Both sensitizing and related Neither alteration OR sensitizing alteration in related patients a OR related alteration in sensitizing patients b p value c
All 44,876 1,682 587 143,102 1.08 1.11 .0001
Ampulla of Vater 69 1 1 151 1.59 2.17 .0001
Bile ducts 1,508 27 12 3,528 1.03 1.04 .0001
Bladder, urothelial tract 1,190 98 51 1,937 0.90 0.85 .0001
Bone 395 1 2 715 1.87 3.61 .0001
Brain 4,349 69 184 5,029 1.57 3.00 .0001
Breast 5,387 194 36 13,928 0.56 0.48 .0001
Cervix 74 9 1 1,369 1.95 2.04 .0490
Colon and rectum 1,684 224 19 19,923 1.00 1.00 .0001
Corpus uteri 532 84 22 6,021 2.56 2.89 .0001
Esophagus, esophagogastric junction 1,804 24 14 2,673 0.91 0.87 .0001
Head and neck 1,088 17 13 2,646 1.49 1.85 .0001
Kidney 869 25 9 2,671 1.08 1.11 .0001
Lung, NSCLC 10,582 197 64 28,810 0.91 0.89 .0001
Melanoma 702 6 3 1,516 1.05 1.08 .0001
Mesothelioma 382 3 1 618 0.65 0.54 .0001
Ovary/peritoneal cancer 1,332 29 6 10,298 1.50 1.60 .0001
Pancreas 3,155 60 23 7,177 0.91 0.87 .0001
Penis 34 2 0 99 0.00 0.00 .0103
Prostate 510 182 10 4,654 0.53 0.51 .0001
Salivary glands 319 9 2 1,004 0.75 0.70 .0001
Skin (nonmelanoma) 216 10 4 1,138 1.79 2.09 .0001
Soft tissue sarcoma 2,044 31 18 5,113 1.29 1.45 .0001
Stomach 789 41 5 2,626 0.47 0.41 .0001
Testis 75 0 0 147 Not calculated Not calculated .0001
Thymus 95 6 3 231 1.14 1.21 .0001
Thyroid 170 33 6 1,502 1.51 1.59 .0122
Unknown primary 4,651 189 62 11,995 0.88 0.85 .0001
Vagina/vulva 107 2 0 360 0.00 0.00 .0001
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Only tumors with a statistically significant association are shown in this table.

a

Odds ratio of a sensitizing cyclin gene alteration (in patients with a related cyclin gene alteration compared with patients with only wild type for cyclin‐related genes).

b

Odds ratio of a related gene alteration in patients with a sensitizing cyclin alteration compared with patients with only wild type for sensitizing cyclin genes.

c

p value for co‐occurrence test.

Abbreviations: NSCLC, non‐small cell lung cancer; OR, odds ratio.

We also analyzed the frequency of hormone pathway–related genes, including ESR1 and AR (supplemental online Figs. 3 and 5). Overall, ESR1 was altered in 1.5% of tumors. Higher frequencies of alterations were noted in breast (11% of breast cancers had an ESR1 alteration) and uterine cancers (3.6%). AR was altered in 0.9% of tumors, and, as expected, prostate cancer presented a high frequency of alterations (20.9%). Surprisingly, AR was also altered (5.7%) in undifferentiated carcinomas. Co‐occurrence of cyclin activating/sensitizing genes and hormone altered genes was analyzed. Diseases with at least 1% of prevalence of hormone receptor alterations are reported (Fig. 4C and supplemental online Table 4). Cervical cancers presented an incidence of 0.6% of ESR1 alterations and 0.3% of AR alterations. These alterations presented significant positive co‐occurrence likelihood with cyclin activating/sensitizing alterations (OR, 4.08; p = .04). In breast cancer we also detected a higher likelihood of co‐occurrence of ESR1 and cyclin activating/sensitizing alterations (OR, 1.63; p < .001) (vs. ESR1 alteration in the presence of wild‐type cyclin activating/sensitizing genes), whereas in prostate cancer a significant co‐occurrence between AR and cyclin activating/sensitizing alterations was detected (OR, 1.79; p < .001) (vs. AR alteration in the presence of wild‐type cyclin activating/sensitizing genes).

Discussion

The cyclin pathway is frequently altered in cancer and may present targeted therapy opportunities. This study represents the largest series (n = 190,247) describing the landscape of genomic abnormalities in different cyclin genes. Overall, we demonstrated that 24% of tumors harbor alterations in genes related to activation/sensitization of the pathway, whereas 10% presented alterations that could lead to resistance to cyclin inhibition (Fig. 1). The frequency of alterations of cyclin genes varied by disease, being highest in brain tumors (47%), esophagogastric cancers (40%), and mesotheliomas (38%), and by histopathology, with highest frequencies in gliomas (54%) and urothelial cancers (41%).

A previous report from our group using a similar genomic analysis, albeit with only 4,864 patients, similarly revealed frequent cyclin gene alterations across cancers [18], as did data on cBioPortal (http://www.cbioportal.org) and other prior smaller series [5, 17].

Unique to this study, SMARCB1 alterations were analyzed as part of the cyclin pathway. In fact, SMARCB1 represses cyclin D1 and inhibits the action of CDK4 resulting in hypophosphorylation of Rb [24, 25]. Overall, we detected alterations in this gene in 0.7% of patients, whereas Memorial Sloan Kettering‐Integrated mutation profiling of actionable cancer targets (MSK‐IMPACT) demonstrated an alteration frequency of 1.3% (n = 10,945) [26]. Mutations in SMARCB1 were first described in malignant rhabdoid tumors [27]. We demonstrated a high frequency of SMARCB1 alterations in tumors with a rhabdoid component (supplemental online Table 3), including brain teratoid rhabdoid tumor (88.4% with alterations), kidney malignant rhabdoid tumor (90%), and extrarenal rhabdoid tumors (63.6%). SMARCB1 inactivation was previously also demonstrated as a characteristic hallmark of renal medullary carcinomas in four cases [28]. Using an NGS approach, we found that 41.3% of these tumors had SMARCB1 genomic alterations (n = 46). Although quite uncommon, SMARCB1 alterations can be detected in a variety of other tumors based on our analysis, especially those neoplasms with a mesenchymal component. Small subsets of tumors can be driven by complete loss of SMARCB1 [29], which offers targeted therapy opportunities, including with CDK4, enhancer of zeste homolog 2, and proteasome inhibition [24, 30].

The large numbers of samples in our series allowed for other interesting observations at both gene and disease levels. CCND2 may be deregulated in testicular germ cell tumors [31], and we demonstrated a high frequency of alterations in CCND2 (mainly amplifications) in germ cell tumors of different origins (23.4% vs. 1.5% overall). About 8.6% of esophageal cancers harbor alterations in CDK6 in our series, which may identify a possible subset of these patients who are resistant to radiotherapy and may be candidates for therapeutic effects of CDK4/6 inhibition [32, 33]. Sarcomas are a heterogeneous group of different tumor subtypes and by and large have been devoid of advances in treatment of systemic disease. Identification of small genomic‐driven subsets is a valid strategy for the treatment of these patients [34]. Regarding the cyclin pathway, soft tissue sarcomas were enriched for CDK4 alterations (12% vs. 3% overall), especially heart sarcomas (38.1% tumors presented alterations); conversely, bone tumors had a high frequency of CCND3 alterations (6.2% vs. 1.4% overall). Cyclin inhibition can be further explored in sarcomas, but patient selection will be essential for therapeutic success [35, 36, 37].

The current regulatory approvals for all three CDK4/6 inhibitors are for hormone‐positive breast cancer, regardless of genomic biomarkers. Exploratory analysis of prospective trials in breast cancer demonstrated that the efficacy of palbociclib was not modulated by CCND1 amplification and cyclin D1, CDK4, or CDK6 expression [38, 39, 40]. For other solid tumors, a phase II basket trial with ribociclib included heavily pretreated patients with advanced cancer and a cyclin genomic alteration (either CDK4/6 mutation or amplification, CCND1/3 amplification, or CDKN2A mutation or loss). Of 106 patients, only three experienced partial responses (soft tissue sarcoma, urothelial carcinoma, and adenocarcinoma) [20]. A prospective trial with palbociclib in patients with pancreatic or biliary cancers with CDKN2A loss or mutation (prevalence in our series of 25.3% and 22%, respectively) also failed to demonstrate activity [21]. So far, these data suggest that targeting cyclin pathway with CD4/6 inhibitors in monotherapy is challenging. Further understanding of genomic co‐alterations in tumors is needed, and as a requisite to that, broad‐based genomic profiling of known sensitivity and resistance determinants as well as exploratory analyses are required [5]. In prostate cancer, crosstalk between androgen signaling and cyclin pathway was suggested, as well as AR independency mediated by cyclin activation [41, 42]. Interestingly, we report a co‐occurrence of AR and cyclin gene alterations, which could identify a subset of patients with more intense resistance to next‐generation antiandrogens. Preclinical rationale suggests further testing of CDK4/6 inhibitors in this setting, as activity of these agents is independent of AR alterations [43]. It is also noteworthy that, for the first time, we report a significant co‐occurrence of ESR1 mutations with cyclin pathway alterations for breast cancer (OR, 1.63; p < .001). Strategies for these patients possibly include selective estrogen downregulators over aromatase inhibitors when combined with CDK4/6 inhibitors [44].

Resistance mechanisms to cyclin inhibition are also important in this setting. Rb1 inactivating mutations may confer resistance to cyclin inhibition and may also emerge during therapy with palbociclib [45]. High CCNE1 mRNA expression was also associated with resistance to this drug [40]. In our series, we demonstrated that possible genomic mechanisms of resistance can be detected in various tumors, especially bladder cancer (20.9%) and nonmelanoma skin cancer (17.9%) for Rb1, and ovarian (12.7%) and esophageal (10.3%) cancers for CCNE1. Interestingly, in the majority of tumors we detected a lower likelihood of co‐occurrence of resistance and sensitizing mutations, which may be interesting for selection of patients for cyclin inhibitors. This finding was also suggested previously analyzing Rb1 alterations [18].

It is important to note that several other genes may interact with the cyclin pathway and, thus, affect cell cycle progression. TP53 is the most frequently mutated cancer gene (64% in our prior report [46]) and is responsible for regulating p21 (CDKN1A) levels via posttranslation mechanisms [47]. MDM2/MDM4 activation can lead to p21 degradation, whereas MDM2 amplification can not only inactivate p53 but also cause Rb1 degradation and E2F1 transactivation [48]. All these events affect the ability of cells to progress from G1 into S phase and could modulate the activity of cyclin inhibitors.

This study has several limitations, including the lack of clinical correlates, which limits elucidating possible associations between genomic alterations and prognosis or response to therapies. The cyclin pathway regulation can also be affected by epigenetic modulation or noncoding genomic alterations [49]. The FoundationOne CDx assay used for this report does not access these alterations, and, therefore, studies are needed to characterize the landscape of epigenetic alterations in the cyclin pathway.

Conclusion

Our analysis shows that alterations in cyclin pathway activating/sensitizing genes occurred in 24% of 190,247 tumors. Specific patterns of alterations differed between tumor types and between patients within any given cancer classification, suggesting the need for individualized characterization of cancers by NGS if these gene alterations are to be optimally exploited in the clinical therapeutic setting. These observations highlight the need for broad‐based profiling of tumors from patients with advanced cancers.

Author Contributions

Conception/design: Denis L. Jardim, Sherri Z. Millis, Razelle Kurzrock

Provision of study material or patients: Denis L. Jardim, Sherri Z. Millis, Jeffrey S. Ross, Michelle Sue‐Ann Woo, Siraj M. Ali, Razelle Kurzrock

Collection and/or assembly of data: Denis L. Jardim, Sherri Z. Millis

Data analysis and interpretation: Denis L. Jardim, Sherri Z. Millis, Razelle Kurzrock

Manuscript writing: Denis L. Jardim, Sherri Z. Millis, Razelle Kurzrock

Final approval of manuscript: Denis L. Jardim, Sherri Z. Millis, Jeffrey S. Ross, Michelle Sue‐Ann Woo, Siraj M. Ali, Razelle Kurzrock

Disclosures

Denis L. Jardim: Roche, Janssen, Astellas, Merck Sharp & Dohme, Bristol‐Myers Squibb, Libbs (H), Janssen, Bristol‐Myers Squibb, Libbs (C/A); Sherri Z. Millis: Foundation Medicine (E, OI); Jeffrey S. Ross: Foundation Medicine (E, OI); Michelle Sue‐Ann Woo: Daiichi Sankyo, Foundation Medicine (E, OI); Siraj M. Ali: Foundation Medicine (E, OI); Razelle Kurzrock: IDbyDNA, CureMatch, Inc., Soluventis (OI), Gaido, LOXO, XBiotech, Actuate Therapeutics, Roche, NeoMed, Soluventis, Pfizer, Merck (C/A), Roche (H), Incyte, Genetech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, DeBiopharm, Boehringer Ingelheim, Omniseq (RF—institutional), CureMatch, Inc., CureMetrix, Inc. (other—board member).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Supporting information

See http://www.TheOncologist.com for supplemental material available online.

Supplemental Figure 1 – Genetic alterations in cyclin resistance genes (RB1 and CCNE1). Specific gene alteration frequencies by histology (A) and by

Supplemental Figure 2 – Chart of alterations (%) in cyclin pathway resistance genes (RB1 and CCNE1). The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 1A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 1B)

Supplemental Figure 3 – Genetic alterations in cyclin related genes (SMAD3, CDKN1A, CDKN1B and CDKN2C) and hormone pathway genes (AR and ESR1). Specific gene alteration frequencies by histology (A) and by disease type (B).

Supplemental Figure 4 ‐ Chart of alterations (%) in cyclin pathway related genes The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 3A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 3B)

Supplemental Figure 5 ‐ Chart of alterations (%) in hormone pathway genes (ESR1 and AR) The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 3A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 3B)

Click here for additional data file. (430.9KB, pdf)

Supplemental Table 1 – Genomic alterations evaluated were classified according to their relationship to the Cyclin pathway

Supplemental Table 2. Analysis of frequency of type of alteration by gene.* Gray highlights indicate alterations that would typically only be identified using comprehensive genomic sequencing.

Supplemental Table 3 – Uncommon tumor types with at least 3 samples tested and presenting a frequency of at least one of the cyclin activating/sensitizing genes that is 3 times the overall frequency described for all samples

Supplemental Table 4 ‐ Co‐incidence of alterations between the cyclin activating/sensitizing genes and hormone pathway genes (ESR1 and AR). Analysis included only tumors with at least 1% of incidence of hormone alterations.

Click here for additional data file. (148.1KB, pdf)

Acknowledgments

This study was funded in part by National Cancer Institute grant P30 CA016672 (to R.K.) and the Joan and Irwin Jacobs Fund Philanthropic Fund.

Disclosures of potential conflicts of interest may be found at the end of this article.

Contributor Information

Denis L. Jardim, Email: denis.ljardim@hsl.org.br.

Razelle Kurzrock, Email: rkurzrock@ucsd.edu.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

See http://www.TheOncologist.com for supplemental material available online.

Supplemental Figure 1 – Genetic alterations in cyclin resistance genes (RB1 and CCNE1). Specific gene alteration frequencies by histology (A) and by

Supplemental Figure 2 – Chart of alterations (%) in cyclin pathway resistance genes (RB1 and CCNE1). The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 1A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 1B)

Supplemental Figure 3 – Genetic alterations in cyclin related genes (SMAD3, CDKN1A, CDKN1B and CDKN2C) and hormone pathway genes (AR and ESR1). Specific gene alteration frequencies by histology (A) and by disease type (B).

Supplemental Figure 4 ‐ Chart of alterations (%) in cyclin pathway related genes The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 3A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 3B)

Supplemental Figure 5 ‐ Chart of alterations (%) in hormone pathway genes (ESR1 and AR) The percent of patients with an alteration are shown. Panel A: Alterations are categorized by histology (This chart corresponds to Supplemental Figure 3A) Panel B: Alterations are categorized by disease type (This chart corresponds to Supplemental Figure 3B)

Click here for additional data file. (430.9KB, pdf)

Supplemental Table 1 – Genomic alterations evaluated were classified according to their relationship to the Cyclin pathway

Supplemental Table 2. Analysis of frequency of type of alteration by gene.* Gray highlights indicate alterations that would typically only be identified using comprehensive genomic sequencing.

Supplemental Table 3 – Uncommon tumor types with at least 3 samples tested and presenting a frequency of at least one of the cyclin activating/sensitizing genes that is 3 times the overall frequency described for all samples

Supplemental Table 4 ‐ Co‐incidence of alterations between the cyclin activating/sensitizing genes and hormone pathway genes (ESR1 and AR). Analysis included only tumors with at least 1% of incidence of hormone alterations.

Click here for additional data file. (148.1KB, pdf)

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