Study population from UK Biobank

A total of 47,550 participants of the UK Biobank program were included in analyses (Fig. 1). The sociodemographic characteristics of enrolled participants were shown in Additional file 3: Table S1. During a median follow-up of 3.11 years, 2894 (6.09%) participants developed second primary cancers, among whom 1763 (60.92%) were males and 1131 (39.08%) were females. Males possessed a higher risk of SPC (HR 1.53, 95% CI 1.42–1.64; P < 0.0001), compared with females (Additional file 4: Fig. S1). Since SEER recommended discriminating metachronous SPC (≥ 2 months) from synchronous one, a total of 2296 (79.34%) cases were classified into metachronous group in the present cohort. The frequency of HLA alleles in the population was shown in Additional file 5: Table S1. The most common HLA allele in the total population was DPA1*01:03. Interestingly, it was also more prevalent in individuals with cancers compared to those without cancers (adjusted P = 0.01 in males and P = 0.0006 in females) (Additional file 5: Table S1 and Additional file 6: Tables S1–11). However, it could not differentiate SPC patients from non-SPC patients. The combinations of HLA alleles were divergent as expected, with totally 263,925 different HLA combinations under 4-digit resolution (Additional file 7: Table S1).

Fig. 1

Flowchart showing the enrollment process of participants. 478,103 participants were included after basic quality control process. 47,550 cancer patients were finally enrolled for analyses based on certain conditions

Screening of SPC-related protective and hazardous HLA alleles

To investigate the relationship between HLA alleles and SPC, univariate logistic regression followed by bidirectional stepwise filtering was performed, yielding the selection of several alleles for multivariable model. Permutation tests were subsequently applied to these alleles (Fig. 2A). The positive beta value in the model defined hazardous HLA alleles while the negative defined protective ones. Two protective alleles (DRB1*04:03, permutation P = 0.001 and DPA1*02:02, permutation P = 0.002) and one hazardous allele (A*26:01, permutation P = 0.031) of SPC were identified for males, while one protective allele (DRB5*01:01, permutation P < 0.0001) and one hazardous allele (DPB1*11:01, permutation P = 0.036) for females (Additional file 1: Table S1). The frequency of the male hazardous allele A*26:01 was 43.06‰ in cancer patients and 41.97‰ in those without cancer (adjusted P value = 0.93). Similarly, for the female hazardous allele DPB1*11:01, no significant difference was found between the cancer and cancer-free groups (adjusted P value = 0.41). Similar results were observed for protective alleles, although DPA1*02:02 was more prevalent among cancer-free male participants (Additional file 6: Tables S1, S4, S5, S8, and S11). Overall, there were no significant differences between the cancer and cancer-free groups for most hazardous and protective alleles, suggesting that these alleles may be specific to SPC.

Fig. 2

Screening of SPC-related protective and hazardous HLA alleles. A Schematic illustrating the screening process. More details could be found in the method section. Cumulative SPC incidence of B males and C females stratified by HLA alleles. Log-rank test was used for statistical analysis. Hazardous alleles: A*26:01 for males and DPB1*11:01 for females. Protective alleles: DRB1*04:03 and DPA1*02:02 for males and DRB5*01:01 for females

The capacity of the identified HLA alleles for SPC prediction was subsequently validated. The presence of protective alleles was associated with a lower risk of SPC compared to individuals without protective alleles for males (HR 0.72, 95% CI 0.59–0.89; P = 0.0019) and females (HR 0.81, 95% CI 0.70–0.93; P = 0.0029). Conversely, the presence of hazardous alleles was linked to an increased risk of SPC for males (HR 1.27, 95% CI 1.03–1.56; P = 0.023) and females (HR 1.35, 95% CI 1.07–1.70; P = 0.011), compared to those without these alleles (Fig. 2B and C). After adjusting several sociodemographic covariates, the estimates of hazardous and protective alleles on SPC were still plausible (Additional file 8: Fig. S1). Collectively, these findings demonstrate that HLA alleles are associated with the risk of SPC and can effectively stratify cancer patients into distinct SPC risk groups.

HLA alleles indicate organ-specific occurrence of metachronous SPC

Metachronous SPC has a delayed onset which provides an opportunity for prediction and prevention. Therefore, we focused on patients whose second cancer developed more than 2 months after the first cancer diagnosis, aiming to identify the factors associated with metachronous incidence. Eleven and thirteen common cancers classified by affected organs were selected for organ-specific analysis for males and females, respectively (Fig. 3A and B and Additional file 9: Table S1). The SPC profile showed that prostate, breast, lung, hematopoietic, and colorectal cancers were the most susceptible second cancers in males and females. Although prostate and breast cancers were the most common first cancers in men and women, respectively, their proportions significantly declined in second cancer diagnoses. In contrast, the incidence of second lung, urinary, hematopoietic, and pancreatic cancers increased notably compared to the initial diagnoses, regardless of gender (Fig. 3C and D). Taken together, these results suggested that metachronous SPC was not merely a result of random incidence. Rather, there may be some underlying factors driving the metachronous association that warrant further investigation.

Fig. 3

Profile of the first and second cancers and organ-specific HLA indication. A–B Heatmap showing the distribution of subsequent cancers. C–D Bar plot showing the changes of constitute ratio in the subsequent setting versus the first setting. The value was presented as the percentage in the second setting minus that in the first. Chi-square test was used for statistical analysis. *P < 0.05, **P < 0.01, and ****P < 0.0001. E Frequency of A*26:01 in second lung cancer male patients divided by first cancer (skin versus others). The Fisher’s exact test was applied with BH multiple comparisons. F Schematic model indicating the role of A*26:01 in skin-to-lung organ-specific SPC incidence. Logistic regression was applied. G Frequency of second lung cancer in first skin cancer patients divided by A*26:01 status

Given that hazardous alleles could increase the risk of SPC and that certain SPCs exhibited higher incidence than expected by chance, we then investigated whether there were some associations between hazardous alleles and the first cancers that contributed to specific second cancers. To achieve this goal, we focused on cancers with second incidence rates exceeding the random background. Results showed that among male patients with second lung cancers, those with first skin cancer had a higher proportion of allele A*26:01 (adjusted P = 0.0057) (Fig. 3E). Furthermore, patients with first skin cancer showed a significantly stronger association with second lung cancer when carrying the A*26:01 allele (Fig. 3F). Additionally, the frequency of patients with first skin cancer developing second lung cancer was significantly higher among those carrying allele A*26:01 than those without it (P = 0.0193, Fig. 3G). These results implied that HLA allele A*26:01 could, at least partly, explain the skin-to-lung organ-specific metachronous association.

A holistic system to minimize SPC hazard through genetic prediction and extragenetic intervention

Based on the above results, we could predict the SPC-susceptible population using HLA alleles. Carriers of hazardous HLA alleles are at a higher risk of developing SPC. In this seminar, we recommended that patients follow specific guideline to reduce their SPC risk, which is more frequent and precise medical examinations if hazardous HLA alleles are detected, rather than relying solely on routine screenings. Additionally, various extragenetic factors have been implicated in cancer development. To investigate the factors influencing cancer patients’ risk of subsequent cancers, we analyzed data related to sociopsychological, behavioral, and dietary aspects (Fig. 4A).

Fig. 4

Forest plot indicating the association between extragenetic factors and SPC. The association between extragenetic factors and SPC incidence estimated by A univariable and B multivariable Cox proportional hazard models. Reference group: physical activity (preferable); smoking and alcohol status (non-current); psychosocial (absence); sugar, fat, protein, and vitamin intake (low intake)

For male patients carrying hazardous HLA allele, higher animal fat intake was associated with an increased SPC risk (HR, 2.44, 95% CI 1.23–4.84; P = 0.01) while higher vitamin C intake correlated with a reduced SPC risk (HR, 0.41, 95% CI 0.2–0.84; P = 0.01) after multivariable adjustment. In female patients, sensitivity to free sugar and vegetable fat was noted. Higher free sugar intake was linked to an increased SPC risk (HR, 2.32, 95% CI 1.04–5.18; P = 0.04) whereas higher vegetable fat intake was associated with a decreased SPC risk (HR, 0.35, 95% CI 0.15–0.80; P = 0.01) (Fig. 4B). These results reveal that there is heterogeneity in dietary susceptibility between male and female cancer patients carrying hazardous SPC-related HLA alleles. We also observed that male patients with hazardous alleles have lower level of lymphocyte count (P = 0.02), but higher level of peripheral neutrophil count (P = 0.05), monocyte count (P = 0.003), and neutrophil–lymphocyte ratio (NLR) (P = 0.002), relative to those with protective alleles, whereas female patients with hazardous alleles have higher level of neutrophils count (P = 0.02) and eosinophils count (P = 0.003), relative to those with protective alleles (Additional file 10: Fig. S1).

Along with HLA prediction, parallel modifications to dietary patterns might contribute to a lower risk of SPC. A Mediterranean-like or Dietary Approaches to Stop Hypertension (DASH)-like pattern is recommended, emphasizing the reduction of animal fat intake and encouraging the use of vegetable oils. Furthermore, for females, minimizing free sugar intake is advisable. Taken together, we proposed an HLA-diet-oriented system that integrated genetic prediction with extragenetic intervention to mitigate the risk of SPC, which might help to achieve the epidemiological goal of primary and secondary prevention of SPC (Fig. 5).

Fig. 5

Schematic model illustrating the HLA-diet-oriented system with genetic prediction and extragenetic intervention against SPC