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Clinical Research Papers:

Prognostic significance of cancer family history for patients with gastric cancer: a single center experience from China

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Oncotarget. 2016; 7:37305-37318. https://doi.org/10.18632/oncotarget.9032

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Xiaowen Liu, Hong Cai, Lin Yu, Hua Huang, Ziwen Long and Yanong Wang _

Abstract

Xiaowen Liu1,2, Hong Cai1,2, Lin Yu2,3, Hua Huang1,2, Ziwen Long1,2 and Yanong Wang1,2

1 Department of Gastric Cancer and Soft Tissue Sarcoma Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

Correspondence to:

Yanong Wang, email:

Keywords: gastric cancer; prognosis; cancer family history

Received: December 16, 2015 Accepted: April 16, 2016 Published: April 26, 2016

Abstract

Family history of cancer is a risk factor for gastric cancer. In this study, we investigated the prognoses of gastric cancer patients with family history of cancer. A total of 1805 gastric cancer patients who underwent curative gastrectomy from 2000 to 2008 were evaluated. The clinicopathologic parameters and prognoses of gastric cancer patients with a positive family history (PFH) of cancer were compared with those with a negative family history (NFH). Of 1805 patients, 382 (21.2%) patients had a positive family history of cancer. Positive family history of cancer correlated with younger age, more frequent alcohol and tobacco use, worse differentiation, smaller tumor size, and more frequent tumor location in the lower 1/3 of the stomach. The prognoses of patients with a positive family history of cancer were better than that of patients with a negative family history. Family history of cancer independently correlated with better prognosis after curative gastrectomy in gastric cancer patients.


Introduction

Despite decreasing incidence and mortality, gastric cancer remains the fifth most common cancer and the third most common cause of cancer-related death worldwide [1]. A number of environmental factors are correlated with gastric cancer development [2-5]. Additionally, a family history of cancer, especially gastric cancer, is associated with increased risk of developing the disease [6, 7]. It is estimated that approximately 13.5% to 46.4% of gastric cancer patients have a family history of cancer [8-10]. Recently, longer overall survival has been reported in other cancer patients with a family history of cancer [11, 12]. Although some studies have reported the clinicopathological features and prognosis of gastric cancer patients with a family history of cancer, these results have been inconsistent [8, 9, 13, 14]. Therefore, the effect of family history of cancer on survival in gastric cancer patients is still unclear. To clarify this question, we conducted this study to evaluate the correlation between family history of cancer and clinicopathologic characteristics and overall survival of gastric cancer patients.

Results

Clinicopathological characteristics

Patients included 1263 males and 542 females (2.3:1) with a mean age of 58 years. There were 339 (18.8%) early gastric cancers and 1466 (81.2%) advanced gastric cancers. Differentiated tumors were observed in 471 (26.1%) patients, and undifferentiated in 1334 (73.9%) patients. 339 (18.8%) were type 0, 9 (0.5%) type I, 502 (27.8%) type II, 879 (48.7%) type III, 76 (4.2%) type IV. Of 1805 patients, 577 (32.0%) had tumors located in the upper third, 298 (16.5%) had tumors in the middle third, 821 (45.5%) had tumors in the lower third of the stomach, and 109 (6.0%) had tumors occupying two-thirds or more of stomach. Lymph node metastasis was observed in 1122 patients (62.2%). The distribution of pathological stage was as follows: 279 (15.5%) patients had stage IA tumors, 216 (12.0%) IB, 186 (10.3%) IIA, 244 (13.5%) IIB, 230 (12.7%) IIIA, 291 (16.1%) IIIB, and 359 (19.9%) IIIC. Patients demographics are listed in Table 1.

Table 1: Patient cohort

n =1805

100%

Sex

Male

1263

70.0

Female

542

30.0

Age (yr)

<60

997

55.2

≥60

808

44.8

Tumor size (cm)

<5

902

61.6

≥5

562

38.4

Histological type

Differentiated

471

26.1

Undifferentiated

1334

73.9

Tumor location

Upper third

577

32.0

Middle third

298

16.5

Lower third

821

45.5

Two-third or more

109

6.0

Borrmann type

0

339

18.8

I

9

0.5

II

502

27.8

III

879

48.7

IV

76

4.2

Vascular tumor emboli

Yes

620

34.3

No

1185

65.7

Nervous invasion

Yes

657

36.4

No

1148

63.6

Pathological stage

IA

279

15.5

IB

216

12.0

IIA

186

10.3

IIB

244

13.5

IIIA

230

12.7

IIIB

291

16.1

IIIC

359

19.9

Family history of cancer

Positive

382

21.2

Negative

1423

78.8

Smoking

Yes

193

10.7

No

1612

89.3

Drinking

Yes

127

7.0

No

1678

93.0

P21 expression

Positive

1134

62.8

Negative

671

37.2

P53 expression

Positive

1319

73.1

Negative

486

26.9

c-myc expression

Positive

1138

63.0

Negative

667

37.0

EGFR expression

Positive

697

38.6

Negative

1108

61.4

Neu/Her-2

Positive

43

2.4

Negative

1762

97.6

Immunohistochemical characteristics

The expression of p21, p53, c-myc, EGFR and Neu/Her-2 was examined by immunohistochemical staining. The location of staining was predominantly in the cell nucleus for p21 and p53, cell cytoplasm for c-myc, cell cytoplasm or membrane for EGFR, and membrane for Neu/Her-2. The positive expression rates of p21, p53, c-myc, EGFR, and Neu/Her-2 were 62.8%, 73.1%, 63.0%, 38.6%, and 2.4%, respectively.

Family history of cancer

Of 1805 patients, 382 (21.2%) had at least one relative with any type of cancer. By cancer type, gastric cancer was the most common and occurred in 190 patients (10.5%), while 192 patients (10.6%) had a family history of other cancers. 348 (19.3%) patients had a family history in first-degree relatives, and 34 (1.9%) in second-degree relatives. In the patients with a family history of gastric cancer, 169 (9.4%) had a family history in first-degree relatives and 21 (1.2%) in second-degree relatives. Data is shown in Table 2.

Table 2: Family histories of cancer in gastric cancer patients

Family history

No. of patients (1805)

%

Cancer

Yes

382

21.2

No

1423

78.8

Relatives

First degree

348

19.3

Second degree

34

1.9

No. of relatives with cancer

1

258

14.3

≥2

124

6.9

Cancer type

Gastric cancer

190

10.5

All other cancers

192

10.6

Gastric cancer

Yes

190

10.5

No

1615

89.5

Relatives

First degree

169

9.4

Second degree

21

1.2

No. of relatives with gastric cancer

1

113

6.3

≥2

77

4.3

All other cancers without gastric cancer

Yes

192

10.6

No

1613

89.4

Relatives

First degree

179

9.9

Second degree

13

0.7

No. of relatives with cancer

1

145

8.0

≥2

47

2.6

Demographic and clinicopathologic features of PFH

Demographically, patients with a positive family history of cancer were younger than patients without positive family history of cancer. There was no difference in gender distribution between the two groups. In patients with a positive family history of cancer, the proportion of smoking and alcohol use was higher than in patients without family history. Clinicopathologically, significant differences were observed in degree of differentiation, tumor location, tumor size, and p21 expression between the two groups. Patients with a positive family history of cancer had a higher rate of undifferentiated tumors and lower 1/3 tumors, smaller tumors, and a lower rate of p21 expression than in those without a positive family history. Data were shown in Table 3.

Table 3: Comparison of the clinicopathological characteristics of patients with positive family history of cancer (PFH) and negative family history of cancer (NFH)

Variables

PFH

n= 382

NFH

n= 1423

P

Gender

0.297

Male

259

1004

Female

123

413

Age (yr)

0.0003

<60

242

755

≥60

140

668

Tumor size (cm)

0.007

<5

267

889

≥5

115

534

Histological type

0.002

Differentiated

76

395

Undifferentiated

306

1028

Tumor location

0.021

Upper third

97

480

Middle third

67

231

Lower third

192

629

Two-third or more

26

83

Borrmann type

0.088

0

88

251

I

3

6

II

93

409

III

180

699

IV

18

58

Vascular tumor emboli

0.483

Yes

137

483

No

245

940

Nervous invasion

0.152

Yes

151

506

No

231

917

Pathological stage

0.207

IA

73

206

IB

47

169

IIA

37

149

IIB

51

193

IIIA

47

183

IIIB

48

243

IIIC

79

280

Smoking

<0.001

Yes

70

123

No

312

1300

Drinking

0.001

Yes

41

86

No

341

1337

P21 expression

0.012

Positive

219

915

Negative

163

508

P53 expression

0.985

Positive

279

1040

Negative

103

383

c-myc expression

0.158

Positive

229

909

Negative

153

514

EGFR expression

0.066

Positive

132

565

Negative

250

858

Neu/Her-2

0.054

Positive

4

39

Negative

378

1384

Kaplan-Meier survival curves by family history of cancer.

Figure 1: Kaplan-Meier survival curves by family history of cancer. There were significant differences between PFH and NFH.

Univariate analysis

The overall 5-year survival rate was 53% for all patients. The 5-year survival rates of PFH and NFH groups were 60% and 52%, and the difference was statistically significant (Figure 1). Additionally, significant prognostic factors included age, differentiation, vascular tumor emboli, nervous invasion, tumor location, tumor size, Borrmann type, TNM stage, family history of gastric cancer, family history of other cancers, p21 overexpression, Neu/Her-2 overexpression, and EGFR overexpression (Table 4). In the PFH group, vascular tumor emboli, nervous invasion, tumor location, tumor size, Borrmann type, TNM stage, p21 overexpression, and c-myc overexpression were significant prognostic factors for survival (Table 5). In the NFH group, age, differentiation, venous tumor emboli, nervous invasion, tumor location, tumor size, Borrmann type, TNM stage, p21 overexpression, Neu/Her-2 overexpression, and EGFR overexpression were significantly correlated with prognosis (Table 6).

Table 4: Univariate analysis of all patients by Kaplan-Meier method.

Variable

n

5-Year survival rate (%)

P value

Sex

0.659

Male

1263

52.4

Female

542

55.4

Age (yr)

<0.001

<60

997

58.9

≥60

808

46.4

Tumor size (cm)

<0.001

<5

1156

62.3

≥5

649

37.4

Histological type

<0.001

Differentiated

471

62.0

Undifferentiated

1334

50.3

Tumor location

<0.001

Upper third

577

41.2

Middle third

298

51.2

Lower third

821

66.1

Two-third or more

109

26.2

Borrmann type

<0.001

0

339

91.3

I

9

40.3

II

502

51.1

III

879

42.8

IV

76

21.1

Vascular tumor emboli

<0.001

Yes

620

31.4

No

1185

64.8

Nervous invasion

<0.001

Yes

657

33.4

No

1148

64.7

Pathological stage

<0.001

IA

279

93.7

IB

216

88.6

IIA

186

66.8

IIB

244

56.8

IIIA

230

47.2

IIIB

291

30.4

IIIC

359

13.0

Smoking

0.061

Yes

193

52.5

No

1612

60.3

Drinking

0.240

Yes

127

57.9

No

1678

53.0

Family history of cancer

0.001

Positive

382

59.8

Negative

1423

51.6

Family history of gastric cancer

0.031

Positive

190

54.2

Negative

1615

43.0

Family history of other cancers

0.038

Positive

192

54.2

Negative

1613

43.0

P21 expression

0.002

Positive

1134

50.5

Negative

671

58.0

P53 expression

0.606

Positive

1319

54.0

Negative

486

51.5

c-myc expression

0.333

Positive

1138

52.4

Negative

667

54.8

EGFR expression

0.006

Positive

697

48.3

Negative

1108

56.3

Neu/Her-2

0.019

Positive

43

30.2

Negative

1762

53.8

Comparison of survival according to tumor stage.

Figure 2: Comparison of survival according to tumor stage. There were significant differences between PFH and NFH according to stage III.

Table 5: Kaplan-Meier univariate analysis of patients with PFH

Variable

n

5-Year survival rate (%)

P value

Sex

0.540

Male

259

57.1

Female

123

65.8

Age (yr)

0.380

<60

242

60.7

≥60

140

58.9

Tumor size (cm)

<0.001

<5

267

67.9

≥5

115

41.3

Histological type

0.160

Differentiated

76

65.9

Undifferentiated

306

57.9

Tumor location

<0.001

Upper third

97

50.3

Middle third

67

61.9

Lower third

192

68.5

Two-third or more

26

23.1

Borrmann type

<0.001

0

88

91.4

I

3

0.0

II

93

63.9

III

180

44.7

IV

18

33.3

Vascular tumor emboli

<0.001

Yes

137

37.6

No

245

71.5

Nervous invasion

<0.001

Yes

151

41.9

No

231

71.2

Pathological stage

<0.001

IA

73

93.8

IB

47

88.8

IIA

37

73.3

IIB

51

60.8

IIIA

47

58.7

IIIB

48

41.7

IIIC

79

13.8

Smoking

0.833

Yes

70

57.3

No

312

60.1

Drinking

0.819

Yes

41

58.5

No

341

59.9

P21 expression

0.041

Positive

219

54.9

Negative

163

66.8

P53 expression

0.535

Positive

279

61.1

Negative

103

55.8

c-myc expression

0.017

Positive

229

54.8

Negative

153

66.8

EGFR expression

0.196

Positive

132

53.0

Negative

250

63.3

Neu/Her-2

0.545

Positive

4

50.0

Negative

378

60.1

Table 6: Kaplan-Meier univariate analysis of patients with NFH

Variable

n

5-Year survival rate (%)

P value

Sex

0.939

Male

1004

51.2

Female

419

52.4

Age (yr)

<0.001

<60

755

58.3

≥60

668

43.8

Tumor size (cm)

<0.001

<5

889

60.5

≥5

534

36.5

Histological type

<0.001

Differentiated

395

60.9

Undifferentiated

1028

47.8

Tumor location

<0.001

Upper third

480

39.2

Middle third

231

47.8

Lower third

629

65.3

Two-third or more

83

26.7

Borrmann type

<0.001

0

251

90.9

I

6

50.0

II

409

48.0

III

699

42.1

IV

58

17.2

Vascular tumor emboli

<0.001

Yes

483

29.5

No

940

62.7

Nervous invasion

<0.001

Yes

506

30.6

No

917

62.9

Pathological stage

<0.001

IA

206

93.4

IB

169

88.6

IIA

149

65.2

IIB

193

55.7

IIIA

183

43.3

IIIB

243

28.2

IIIC

280

12.8

Smoking

0.050

Yes

123

60.9

No

1300

50.6

Drinking

0.334

Yes

86

57.1

No

1337

51.1

P21 expression

0.031

Positive

915

49.4

Negative

508

55.4

P53 expression

0.781

Positive

1040

52.0

Negative

383

50.2

c-myc expression

0.781

Positive

909

51.8

Negative

514

51.1

EGFR expression

0.023

Positive

565

47.4

Negative

858

54.3

Neu/Her-2

0.037

Positive

39

28.2

Negative

1384

52.2

Multivariate analysis

Multivariate analysis showed that family history of cancer, age, tumor differentiation, vascular tumor emboli, Borrmann type, tumor size, TNM stage, and p21 overexpression were independent prognostic factors for all patients (Table 7). In the PFH group, TNM stage and c-myc overexpression were significant prognostic factors (Table 8). In the NFH group, age, differentiation, vascular tumor emboli, and TNM stage were independent prognostic factors (Table 9).

Table 7: Multivariate analysis of patients by Cox model.

Variable

P value

RR

95% CI

Age

<0.001

1.327

1.170-1.505

Histological type

0.007

1.234

1.060-1.437

Vascular tumor emboli

0.005

1.225

1.065-1.409

Nervous invasion

0.149

1.108

0.964-1.273

Tumor location

0.081

0.944

0.885-1.007

Borrmann type

0.041

1.093

1.004-1.191

Tumor size

0.035

1.149

1.010-1.308

Pathological stage

<0.001

1.464

1.400-1.532

Family history of cancer*

0.033

0.836

0.708-0.986

Family history of gastric cancer*

0.309

0.891

0.714-1.113

Family history of other cancers*

0.073

0.817

0.655-1.019

P21

0.045

1.146

1.003-1.309

EGFR

0.183

1.091

0.960-1.240

Neu/Her-2

0.173

1.287

0.895-1.851

* Only one parameter can be put into Cox proportional hazards model very time.

Table 8: Multivariate analysis of patients with PFH.

Variable

P value

RR

95% CI

Vascular tumor emboli

0.109

1.312

0.942-1.830

Nervous invasion

0.506

1.120

0.802-1.562

Tumor location

0.404

0.934

0.796-1.096

Tumor size

0.165

1.253

0.911-1.724

Borrmann type

0.097

1.184

0.970-1.445

Pathological stage

<0.001

1.452

1.305-1.617

P21

0.094

1.307

0.955-1.787

c-myc

0.028

1.424

1.039-1.953

Table 9: Multivariate analysis of patients with NFH.

Variable

P value

RR

95% CI

Age

<0.001

1.393

1.212-1.601

Histological type

0.005

1.270

1.077-1.499

Vascular tumor emboli

0.019

1.203

1.030-1.405

Nervous invasion

0.182

1.110

0.952-1.293

Tumor location

0.115

0.944

0.880-1.014

Tumor size

0.085

1.133

0.983-1.305

Borrmann type

0.140

1.074

0.977-1.180

Pathological stage

<0.001

1.469

1.397-1.544

P21

0.171

1.108

0.957-1.284

EGFR

0.140

1.112

0.966-1.280

Neu/Her-2

0.188

1.287

0.884-1.876

Comparison of survival according to stage between PFH and NFH groups

According to the AJCC/TNM staging, gastric cancer patients were divided into stage I, stage II, and stage III. According to family history of cancer, each stage was divided into PFH and NFH groups. There was a statistically significant difference in overall survival between the PFH and NFH groups for patients with stage III tumors (P <0.05, Figure 2).

Discussion

Familial aggregation is quite common in all kinds of cancers. In this study, 21.2% of gastric patients had a positive family history of cancer. This is similar to that reported in previous studies [8-10]. The reason for familial aggregation is unclear. It is possible that environmental factors or genetic factors contribute to this. Some studies have shown that environmental factors such as diet or socioeconomic status were significantly associated with risk of family gastric cancer [15, 16]. Additionally, Some studies have reported that microsatellite instability (MSI) was associated with family history of gastric cancer [17, 18]. Lee et al. reported that p53 overexpression may increase familial aggregation of gastric cancer [8]. In the current study, we examined expression of some genes, and we found that p21 expression by tumor cells correlated with family history of gastric cancer. Further study is needed to elucidate the mechanism.

In this study, we found that gastric cancer patients with family history of cancer had different clinicopathological features compared to those without a family history of cancer. Our results showed that patients with a family history of cancer were younger than patients without family history of cancer. However, this result was inconsistent with that reported by a Korean study [9], which found that there was no significant difference in mean ages between familiar gastric cancer and sporadic cancer. It is possible that difference is due to the bias of self-reported family history. Another two recent studies have confirmed our results [19, 20]. Additionally, we found that patients with positive family history of cancer had a higher rate of lower 1/3 tumors. Inoue et al [21] also reported that tumors were more frequently located in the lower and middle part of the stomach in gastric cancer patients with a positive family history. In all, the differences of clinicopathological features and some genes expression between two groups indicated that gastric cancer with positive family history may represent a distinct disease.

Although some studies have reported the effects of a positive family history on the survival of patients with gastric cancer, the results were controversial [8, 9, 13, 14]. These inconsistencies might be due to the adjustment range of confounding variables. Additionally, it might be explained by low statistical power as a result of small-scale sample. In our study, family history of cancer was consistently associated with prognosis in both univariate and multivariate analyses after adjustment for prognostic variables. It is not clear why a family history of cancer increase survival. It is possible that a family history of cancer may heighten awareness of gastric cancer in family members, leading to earlier diagnosis and better prognosis. We found that patients with a positive family history were more likely to have smaller tumor size. However, the current study could not confirm this hypothesis as a result of no information about previous screening. Some studies have shown that patients with a family history of cancer are more likely to undergo cervical cancer and prostate cancer screening [22, 23]. Additionally, health behaviour may also have contributed to the better survival of patients with family history of cancer. Patients with a family history of cancer more likely to have good behavioural habits, like quitting smoking, or healthy dietary habits [24, 25]. Given the fact that smoking and drinking habits are associated with poor prognosis in gastric cancer, a reduced incidence of unhealthy behaviour may partly account for improved prognosis. Han et al. reported that proportions of current smokers or drinkers were significantly lower in patients with a family history of cancer[9]. In contrast, we found that proportions of smokers or drinkers were significantly higher in patients with family history, and smoking or drinking did not affect the survival of gastric cancer patients. Therefore, the effect of health behaviour on prognosis needs further investigation. Finally, genetics may also account for the survival differences of gastric cancer patients with a family history. Microsatellite instability (MSI) is detected frequently in gastric cancer. It has been reported that MSI is associated with a family history of gastric cancer and better overall prognosis [17, 18, 26]. In this study, expressions of p21, p53, c-myc, EGFR and Neu/Her-2 were examined by immunohistochemical staining. We found that rate of p21 expression was lower in patients with family history. In addition, multivariate analysis showed that p21 expression was an adverse independent prognostic factor for gastric cancer. These results indicated that low expression of p21 contributed to the good prognosis of gastric cancer patients with family history of cancer. However, the exact mechanism is unclear, and further study is needed.

A limitation of our study is that it has relied on self-reported family history, and the family history information was not confirmed pathologically. However, we confirmed the family history by asking patients’ relatives in order to reduce the probability of under-reports or over-reports. Secondly, we did not investigate genetic mutations for MSI or CDH1.

In conclusion, our study showed that the prognosis of gastric cancer patients with a family history of cancer was better than that of patients without a family history. Given the association of p21 expression and family history of cancer, this result may facilitate further development of agents targeting p21 expression and clinical trials evaluating the role of these agent in gastric cancer patients with a family history of cancer.

Materials and Methods

Patients

From 2000 to 2008, 1805 patients with histologically confirmed primary gastric adenocarcinoma underwent curative gastrectomy at the Department of Gastric Cancer and Soft Tissue Sarcoma Surgery, Fudan University Shanghai Cancer Center. Exclusion criteria for this study were as follows: (1) surgery status unknown; (2) vital status unknown; (3) uncompleted pathological data. Data were retrieved from operative and pathological reports. Follow-up data were obtained by phone, outpatient visits and our clinical database. Written informed consent was obtained from all patients, and this study was approved by the Ethical Committee of Fudan University Shanghai Cancer Center. Staging was done according to the American Joint Committee on Cancer (AJCC) TNM Staging Classification for Carcinoma of the Stomach (Seventh Edition, 2010). Gastrectomy was performed in accordance with the Japanese Classification of Gastric Carcinoma.

Immunohistochemical staining

The expression of p21, p53, c-myc, EGFR, and Neu/Her-2 in primary lesions was detected by immunohistochemical staining. All primary antibodies and mouse monoclonal antibodies were purchased from Dako (Hamburg, Germany). The detailed sources, concentrations of antibody and positive site were as follows: anti-p21 (clone SX118), 1:50 dilution, nucleus; anti-p53 (clone DO-7), 1:100 dilution, nucleus; anti-c-myc (clone 9E10), 1:100 dilution, cytoplasm; anti-EGFR (clone E30), 1:50 dilution, cytoplasm or membrane; anti-Neu/Her-2 (clone PN2A), 1:100 dilution, membrane. The staining experiments followed the supplier’s instruction. Negative controls were subjected to the same procedure except that the first antibody was replaced by PBS.

Immunohistochemical staining scores

All slides were evaluated by pathologists without knowledge of patients’ clinical data. The percentage of immunoreactive cells was graded on a scale of 0 to 4: no staining was scored as 0, 1-10% of cells stained scored as 1, 11-50% as 2, 51-80% as 3, and 81-100% as 4. The staining intensities were graded from 0 to 3: 0 was defined as negative, 1 as weak, 2 as moderated, and 3 as strong, respectively. An IHS score of 9-12 was considered as strong immunoreactivity (+++), 5-8 as moderate (++), 1-4 as weak (+), and 0 as negative (-). On the final analysis, the cases with a score of less than 1 were considered as negative, and ≥ 1 was regarded as positive. These criteria were based on our previously published results [27].

Family history evaluation

Family history of cancer was reviewed from the patient interview record. A positive family history of cancer was defined as a history of cancer within second-degree relatives. First-degree relatives were defined as parents, siblings, or offspring, and second-degree relatives were defined as aunts, uncles, nieces, nephews, or grandparents.

Follow-up

Follow-up of all patients was carried out according to our hospital’s standard protocol (every three months for at least 2 years, every six months for the next 3 years, and after 5 years every 12 months for life). The check-up items included physical examination, tumor-marker examination, ultrasound, chest radiography, computed tomographic scan, and endoscopic examination. The median follow-up time was 72 months for all patients.

Statistical analysis

The patients’ features and clinicopathological characteristics were analyzed using the X2 test for categorical variables. Five-year survival rate was calculated by the Kaplan-Meier method, and the differences between survival curves were examined with the log-rank test. Independent prognostic factors were examined by the multivariate survival analysis using the Cox proportional hazards model. The accepted level of significance was P <0.05. Statistical analyses and graphics were performed using the SPSS 13.0 statistical package (SPSS, Inc., Chicago, IL).

Acknowledgments

The authors thank Ben Liotta for editing our manuscript’s English language style, and the patients for their participation in this study.

Conflicts of interest

The authors declare no competing financial interests.

Grant support

This research is supported by grants from the Shanghai Committee of Science and Technology Funds (Contract grant numbers: 14ZR1407800), and the National Natural Science Foundation of China (81502027). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.

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