High-grade serous carcinoma of the fallopian tube in a young woman with chromosomal 4q abnormality: A case report

Abstract

BACKGROUND

Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome. This study presents a rare association between chromosome 4q abnormalities and fallopian tube high-grade serous carcinoma (HGSC) in a young woman.

CASE SUMMARY

A 35-year-old woman presented with acute dull abdominal pain and a known chromosomal abnormality involving 4q13.3 duplication and 4q23q24 deletion. Upon arrival at the emergency room, her abdomen appeared ovoid and distended with palpable shifting dullness. Ascites were identified through abdominal ultrasound, and computed tomography revealed an omentum cake and an enlarged bilateral adnexa. Blood tests showed elevated CA-125 levels. Paracentesis was conducted, and immunohistochemistry indicated that the cancer cells favored an ovarian origin, making us suspect ovarian cancer. The patient underwent debulking surgery, which led to a diagnosis of stage IIIC HGSC of the fallopian tube. Subsequently, the patient received adjuvant chemotherapy with carboplatin and paclitaxel, resulting in stable current condition.

CONCLUSION

This study demonstrates a rare correlation between a chromosome 4q abnormality and HGSC. UBE2D3 may affect crucial cancer-related pathways, including P53, BRCA, cyclin D, and tyrosine kinase receptors, thereby possibly contributing to cancer development. In addition, ADH1 and DDIT4 may be potential influencers of both carcinogenic and therapeutic responses.

Key Words: High-grade serous carcinoma, Fallopian tube, Young age, Chromosomal abnormality, Mental retardation, Aging, Case report

Core Tip: In this report, we present a case of high-grade serous carcinoma (HGSC) in the fallopian tube of a young woman, associated with a chromosomal 4q abnormality. We provide updated insights on the symptoms, signs, diagnosis, and treatment specific to HGSC linked with chromosomal abnormalities. Given the rare nature of chromosomal abnormality-associated HGSC, we have formulated a strategic approach for its diagnosis and management.

INTRODUCTION

Ovarian cancer had been the fifth most common cancer in women and the fourth most common cause of cancer-related deaths in women from 1999 to 2009 in the United States[1,2]. Epithelial ovarian tumors comprise 90% of ovarian cancers, of which approximately 80% are serous carcinomas that arise from the fallopian tube epithelium[1-3]. Epidemiological data have shown that the oldest age during which ovarian cancer is detected is 60-65 years in the United Kingdom and Taiwan, with 90% of cases occurring after 45 years of age[4,5]. Numerous factors contribute to an increased risk of ovarian cancer. These include early onset of menstruation (early menarche), delayed cessation of menstrual cycles (late menopause), a family history of breast or ovarian cancer, and mutations in the BRCA1 or BRCA2 genes[6-8]. Early-stage ovarian cancers are often asymptomatic, whereas mild or frequent symptoms such as gastrointestinal discomfort, abdominal pain or masses, loss of appetite and weight, abnormal vaginal bleeding, and dyspnea due to pleural effusion occur in more advanced cases[9]. Although the exact causes of ovarian cancers remain unclear, different gene mutations allowing us to distinguish between high- and low-grade serous ovarian carcinomas have been identified through pathology[2,10]. Thus, genetic mutations may be critical in serous ovarian carcinomas.

Chromosome 4 is a large chromosome that contains multiple critical protein-coding genes[11,12]. Interstitial or terminal deletion of 4q results in 4q deletion syndrome, also called 4q syndrome, which is a rare chromosomal disorder with an estimated incidence of 1 per 100000 people[13]. The most common phenotypes of 4q deletion syndrome typically involve anomalies in craniofacial, digital, skeletal, and cardiac features, and this condition is associated with a mortality rate of approximately 23%[14-17]. Most surviving probands show delayed neurodevelopment and antenatal or postnatal growth deficiencies[15]. However, in some patients, slow growth and intellectual disability may occur without any apparent physical abnormalities, making it difficult to recognize this disorder[18].

Owing to its rarity and frequent underdiagnosis, few studies have identified an association between an increased risk of developing cancers and 4q deletion syndrome. Herein, we report a rare association between chromosome 4q abnormality and high-grade serous carcinoma (HGSC) of the fallopian tube in a 35-year-old woman.

CASE PRESENTATION

Chief complaints

Acute abdominal dull pain was noted.

History of present illness

A 35-year-old female with a chromosomal abnormality (4q13.3 duplication and 4q23q24 deletion) had been in her usual state of health until a month ago. Her activities of daily living were partially dependent, and she was able to attend the daycare center for education. One month before admission, she experienced abdominal distension without diarrhea, vomiting, and changes in eating habits. Thus, her mother visited a pharmacy and bought symptom-relieving medications.

She had a sudden onset of acute dull abdominal pain at the right upper quadrant, without specific precipitating or relieving factors. She rated her pain as an 8/10 and mentioned that it kept her up at night. Her mother immediately visited the emergency department of our hospital for evaluation.

History of past illness

Five years ago, the patient first visited our hospital because of cataract due to phacoemulsification in both eyes at 30 years of age. Four years prior, she visited our pediatric outpatient department as she did not experience her menstrual cycle for a year. Our pediatrician found that her hand joints were contracted and deformed. Unintentional body weight loss of 30 kg/year, moderate mental retardation, and delayed development without a rehabilitation program were also observed. Her karyotype was 46, XX with normal metabolic and hormone disease screening test results. Complete blood count test found that she had microcytic anemia with a family history of alpha thalassemia from her father's side. Blood electrophoresis revealed normal hemoglobin (Hb) A1, HbA2, and HbH levels.

After receiving education on nutritional support, her menstrual cycles returned to normal. Two years ago, her menstrual cycle became absent again, and her pelvic echogram showed a right ovarian cyst approximately 1.3 cm² × 1.4 cm² in size without other positive findings. Whole-exome sequencing revealed 46 XX, 4q13.3 duplication, and 4q23q24 deletions affecting multiple genes (Figure 1).

Figure 1 Next-generation sequencing of the whole exome. A: Copy numbers in all chromosomes; B: Duplication in chromosome 4q13.3 from 73004016 to 73138249 could have possibly affected the ANKRD17 and COX18 genes; C: Deletion in 4q23q24 from 99214690 to 103455006 could have possibly affected the ADH1A, ADH1B, ADH1C, ADH6, ADH7, BANK1, C4orf54, CENPE, CISD2, DAPP1, DDIT4L, DNAJB14, EMCN, H2AZ1, LAMTOR3, MANBA, MTTP, NFKB1, PPP3CA, SLC39A8, SLC9B1, SLC9B2, TRMT10A, and UBE2D3 genes.

Radiography of her joints showed osteoarthritis of the bilateral hip joints with large subchondral cysts at the right acetabular roof and femoral head; osteoarthritis of the bilateral knee joints; multiple joint destruction, deformity, and subluxation at most of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints in both hands; and diffuse joint space narrowing with subchondral and marginal erosions at the radiocarpal joint and intercarpal joints of bilateral wrists. She had come for regular follow-up 1 year prior.

The patient complained of frequent abdominal bloating and constipation. Amenorrhea was also observed for half a year.

Personal and family history

The patient was a freelance worker, nonsmoker, and nonalcoholic consumer and had regular menstrual cycles since she was 12 years of age. Her parents had no history of cancer. Her uncle and grandmother had skin cancer and leukemia, respectively. She had a brother 5 years older, who was mentally and physically normal.

Physical examination

On examination, the patient was alert and fully oriented. Her temperature was 36.2 °C, blood pressure was 100/60 mmHg, pulse was 82 beats per minute, respiratory rate was 20 breaths/min, and oxygen saturation was 97% while breathing room air. The patient was malnourished and pale. Her height, weight, and body mass index were 145 cm, 37 kg, and 17.6 kg/m², respectively. The abdomen was ovoid and distended. Bowel sounds are typical in auscultation. A tympanic sound was heard at the top of the abdomen but it did not become dull when shifting downwards. A shifting dullness test was performed thereafter, showing positive findings. Abdominal tenderness was observed only in the right upper quadrant without rebounding pain, and Murphy’s sign was negative. Her heart sounds were regular and without murmurs. Breathing sounds with pleural friction rubs were auscultated in the bilateral lung fields. Her extremities were warm, with pitting edema. Her right hip showed a decreased range of motion and muscle power, which were otherwise normal in the knees, shoulders, elbows, and left hip. Her hands contracted with stiffness at the metacarpal phalangeal, proximal interphalangeal, and distal interphalangeal joints and bilateral radiocarpal and intercarpal joints. The capillary refilling time of the toe was > 2 s. Results of the remaining examinations were normal.

Laboratory examinations

Laboratory analyses revealed microcytic anemia, hypoalbuminemia, hypoproteinemia, and elevated C-reactive protein levels. Cancer markers showed increased cancer antigen 125 (241.7 U/mL), while the other markers were within the normal reference range. Paracentesis showed cloudy ascites with a white blood cell count of over 1000 cells/μL. Moreover, the amylase level in ascites was below 1000 IU/L, suggesting the absence of pancreatic ascites. The serum-ascites albumin gradient was 0.5 g/dL, suggesting that ascites was not caused by portal hypertension. Culture and gram staining results were negative for bacterial infections (Table 1).

Table 1 Values of laboratory examinations.

Variable	On admission	Reference range
Hematocrit (%)	31.5	36-46
Hemoglobin (g/dL)	8.7	12-16
White cell count (μL)	10480	3500-11000
Prothrombin time (s)	9.9	8-12
Total protein (g/dL)	5.1	6.4-8.9
Albumin (g/dL)	3.3	3.5-5.7
CRP (mg/dL)	9.39	< 1
AFP (ng/mL)	1.9	< 9
CEA (ng/mL)	0.3	< 3
CA125 (U/mL)	241.7	< 35
CA19-9 (U/mL)	2.7	< 35
	Ascites
Appearance	Cloudy	-
WBC count (μL)	1087	-
Amylase (IU/L)	134	-
Albumin (g/dL)	2.6	-
Gram stain	Negative	Negative
Bacteria culture	No growth	No growth

CRP: C-reactive protein; AFP: Alpha-fetoprotein; CEA: Carcinoembryonic antigen; CA125: Cancer antigen 125; CA19-9: Cancer antigen 19-9; WBC: White blood cell.

Imaging examinations

Kidney, ureter, and bladder radiography showed hydroperitoneum. Computed tomography from the lower chest to the pelvis revealed carcinomatous peritonitis and an omental cake.

FINAL DIAGNOSIS

Stage IIIC HGSC of the fallopian tube.

TREATMENT

With the impression of secondary bacterial peritonitis of unknown origin, pelvic ultrasonography was performed, demonstrating increased bilateral adnexal mass with carcinomatosis in the cul-de-sac. Additional immunohistochemical staining of the ascites showed CK7(+), CK20(-), CDX2(-), PAX8(-), and TTF-1(-) expression, indicating that the cancer may have originated from the ovaries. Staging surgery for ovarian cancer was performed using frozen-section pathology, demonstrating HGSC. Histopathological examination confirmed that the primary site was the right fallopian tube, showing serous tubal intraepithelial carcinoma and HGSC (Figure 2). Moreover, HGSC was found in the bilateral ovaries, uterine corpus, greater omentum, peritoneum, bilateral pelvic lymph nodes, para-aortic lymph nodes, and appendix. The tumor size in the bilateral ovaries was > 2 cm with lymph node metastasis to the paraaortic lymph nodes (pT3cN1a, FIGO stage IIIC). Additional immunohistochemical staining of the tumor revealed mutational overexpression of p53 (Figure 3) and strong positive estrogen receptor expression (60%). MSH6 and PMS2 proteins retained expression in the nucleus.

Figure 2 Serous tubal intraepithelial cancer and high-grade serous carcinoma. Scale bar = 200 μm. A: Serous tubal intraepithelial cancer; B: High-grade serous carcinoma. Scale bar = 100 μm.

Figure 3 Immunohistochemistry of P53 in high-grade serous carcinoma. Scale bar = 200 μm.

OUTCOME AND FOLLOW-UP

Postoperatively, she received two courses of chemotherapy with carboplatin (dosage: area under the curve = 5) and paclitaxel (dosage: 135 mg/m²). However, pancytopenia was observed after the first course of chemotherapy. She recovered after subcutaneous injection of granulocyte colony-stimulating factor, packed erythrocytes, and platelet transfusion. The chemotherapy dose was reduced to 80% of the standard dose. The patient was closely monitored thereafter. The patient's symptom onset and diagnostic timeline are presented in Table 2.

Table 2 The patient's symptom onset and the diagnostic timeline.

Year-old	Incident
12	Menarche
26	No mense for one year, hand joints were contracted and deformed, Unintentional body weight loss of 30 kg/year, moderate mental retardation, and delayed development
26	Karyotype was 46, XX
30	Cataract due to phacoemulsification in both eyes
33	The menstrual cycle became absent again
33	NGS showed 4q13.3 duplication, and 4q23q24 deletions
35	High-grade serous carcinoma of the ovary, stage IIIC

DISCUSSION

Chromosome 4q defects, including deletions, loss of heterogeneity, and translocations, have been observed in colon, lung, and multiple myeloma cancer tissues, including deletion, loss of heterogeneity, and translocation[19-21]. Frequent loss of chromosome 4q has been observed in the analysis of ovarian cancer cell lines and tissues using comparative genetic hybridization[22,23]. However, the critical mutated genes in aggressive HGSCs are TP53 and BRCA on chromosome 17[2,10]. Few studies have shown that the loss of critical genes in 4q deletions results in an increased risk of developing HGSC. To our knowledge, this study is the first to report the potential association between specific genes within the critical region of the 4q23q24 deletion and HGSC, as well as multiple aging-related diseases, such as osteoarthritis and cataracts.

In our case, the patient lost one copy of the 4q23q24 region, which affected multiple genes, as listed in Table 1. Several of the genes involved may be associated with HGSC. The ubiquitin-conjugating enzyme E2 D3 (UBE2D3) gene encodes the UBE2D3 protein (Ubc5Hc), which regulates ubiquitination[24]. Ubiquitination targets proteins for proteasomal degradation and requires the thioester cascade of the E1-E2-E3 complex to transfer ubiquitin to target proteins[25]. Recent studies have shown that the ubiquitination and deubiquitination of multiple pathways are associated with tumorigenesis and cancer metabolism[26,27]. BRCA proteins are essential for repairing DNA mutations that have been found to increase the risk of ovarian cancer[28]. The RING domain in the BRCA1-BARD1 protein orients the UBE2D3 protein towards the ubiquitination of H2A for homologous recombination to repair DNA double-strand breaks[29]. Moreover, mutations in the BRCA1-BARD1 RING domain have been linked to familial breast and ovarian cancer, showing that structural compactness and reduced significant interactions may be a possible reason for cancer by preventing ubiquitination and hindering DNA repair[30].

P53 mutations are commonly observed in advanced ovarian cancers, as in our case[31]. Mutations in the TP53 gene encodes the mutant P53 protein, which mainly induces mutations affecting cell proliferation or mutagen exposure[32]. The mutant P53 protein loses its wild-type tumor-suppressive function and acquires oncogenic properties, enabling tumor metastasis, proliferation, and cell survival[33]. Moreover, mutant p53 exerts dominant-negative activity by abrogating DNA binding and growth suppression of wild-type p53[34]. Mutant p53 is regulated by many of the same signals that regulate wild-type p53[35]. The loss of degrading enzymes of wild-type p53, including murine double minute 2 (Mdm²), an E3 ubiquitin ligase that targets p53 for proteolytic degradation, stabilizes mutant p53, resulting in an earlier age of tumor onset in mice[36]. UBE2D3 protein knockdown causes the accumulation of Mdm² and p53 in unstressed cells and inhibits the MDM2-mediated ubiquitin-proteasome degradation of p53[37]. In human breast cancer cells, UBE2D3 protein knockdown reduces ubiquitination of cyclin D1, resulting in increased proliferation and cell invasiveness[38]. UBE2D3 also has ubiquitinated tyrosine kinase receptors that are commonly dysregulated in HGSC[39,40]. In summary, the downregulation of UBE2D3 impairs the ubiquitination of multiple proteins, including P53, BRCA, Cyclin D, and tyrosine kinase receptors, with some losing their function, which may lead to cancer.

The class 1 alcohol dehydrogenase (ADH1) family is associated with ovarian carcinogenesis and peritoneal metastasis. ADH1B enhances various factors that additionally facilitate the progression of ovarian cancer[41]. The drug metabolism-associated gene ADH1B and its interactive network are crucial for immune regulation and therapeutic responses[42]. ADH1B downregulation has been observed in ovarian cancer. Therefore, it may be a potential therapeutic target in patients with ovarian cancer. ADH1B downregulation could be linked to drug resistance[43]. Our patient had an ADH1B deletion.

DDIT4 overexpression increases recurrence risk by 18%[44]. DDIT4 may be involved in antitumor therapy resistance, proliferation, and invasion in numerous cancers and participates in DNA-damage repair in specific conditions[45]. Therefore, DDIT4L was deleted in this patient, which may have led to carcinogenesis.

Besides HGSC, the early onset of senile diseases such as cataracts in both eyes and osteoarthritis in the hip in her 30s may have been caused by the deletion of the CISD2 gene. The expression levels of CISD2 decrease in an age-dependent manner during natural aging. CSID2 knockout drives premature aging by causing mitochondria-mediated defects in mice[46]. The lifespan of mice was extended after achieving a persistent level of CISD2 via transgenic expression[47]. Impaired osteogenic differentiation has been observed in CISD2-deficient murine-induced pluripotent stem cells, contributing to the pathogenesis of osteopenia and the lordokyphosis phenotype in CISD2 knockout mice[48]. Mitochondrial dysfunction in chondrocytes derived from CISD2 knockout murine-induced pluripotent stem cells leads to decreased extracellular matrix and increased reactive oxygen species formation, which is commonly observed in the aged chondrocytes of patients with osteoarthritis[49]. Nevertheless, no study has reported that CISD2 deficiency induces cataracts. CISD2 deficiency affects human corneal epithelial cells and impairs epithelial regeneration[50]. These results indicate that CISD2 gene deletion may be associated with premature aging diseases, which may require further attention in our patients for the onset of certain conditions.

CONCLUSION

This study revealed a rare correlation between chromosome 4q abnormality and fallopian tube HGSC in a 35-year-old woman. UBE2D3 is implicated in cancer-related pathways, affecting P53, BRCA, cyclin D, and tyrosine kinase receptors, and potentially contributing to cancer development. ADH1 and DDIT4 are factors that influence carcinogenesis and therapeutic responses. The clinical significance lies in uncovering this rare association in young individuals and providing insights into key cancer pathways. These findings may affect the diagnosis, prognosis, and treatment strategies for HGSC with similar genetic abnormalities, emphasizing the need for personalized approaches in ovarian cancer management. Further research is required to identify novel therapeutic targets for tailored treatment.

ACKNOWLEDGEMENTS

We thank Dr. Yu-Tai Shih for his assistance with X-ray reading.