Clinical Characteristics and MPT Combinations
460 individuals (106 [23%] males and 354 [77%] females) in 440 families had been diagnosed with 1,143 primary tumors distributed among 87 categories according to site and cell of origin. The most frequent tumor types are illustrated in Table 2 (comprehensive lists are provided in Tables S1 and S5). Representing 24.6% of the total, breast cancer was the most frequent tumor, and colorectal cancer was the second (9.9%). Prior genetic testing is described in Table S6, and reasons for non-detection of the relevant variant are illustrated in Figure 2.
Figure 2 Molecular Investigations Initiated by Clinical Services with Inferred Reasons for Non-detection of Variants
Table 2 Most Frequent Tumors and Tumor Combinations in the Series
Tumor Category Count Percentage (%)
>5% Total (n = 1,143)
Breast 281 24.6
Colorectal 113 9.9
Kidney 83 7.3
NMSC 67 5.9
Ovary 58 5.1
>1% Total (n = 883)
Breast-colorectal 51 5.8
Breast-NMSC 35 4.0
Breast-ovary 34 3.9
Breast-endometrium 33 3.7
Breast-hem lymphoid 26 2.9
Breast-melanoma 24 2.7
Breast-thyroid 23 2.6
Endometrium-ovary 19 2.2
Breast-kidney 18 2.0
Colorectal-NMSC 14 1.6
Breast-lung 12 1.4
NMSC-hem lymphoid 11 1.2
Breast-soft tissue sarcoma 10 1.1
Colorectal-endometrium 9 1.0
Kidney-pituitary 9 1.0
Kidney-thyroid 9 1.0
Melanoma-NMSC 9 1.0
The following abbreviations are used: hem lymphoid, hematological lymphoid; and NMSC, non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma).
The occurrence of any two discordant primary tumors in the same individual was considered a tumor combination, and a total of 883 combinations and 327 combination types were observed (individuals with three or more discordant tumors had multiple combinations). 206 (63%) combination types occurred once, and 53 (16.2%) occurred twice. The 68 (20.8%) combination types occurring three or more times are illustrated in Figure 3. The most frequent combination type was breast and colorectal cancer, which represented 5.8% of the total combinations. All combination types making up ≥1% of the total are shown in Table 2.
Figure 3 Most Frequent Tumor Combination Types
Combination types occurring fewer than three times are not included. Abbreviations are as follows: pheo, pheochromocytoma; GI NET, gastrointestinal neuroendocrine tumor; hem myeloid, hematological myeloid; PNET, pancreatic neuroendocrine tumor; hem lymphoid, hematological lymphoid; and NMSC, non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma).
To compare the distributions of tumor combinations in our MPT study cohort with a population-based dataset, we compared 313 MPT cohort individuals comprising 523 combinations with 471 individuals comprising 574 combinations in the East Anglia Cancer Registry data (Table S7). There was a significant difference (χ2 p value < 0.05) in the frequency of tumor combinations in 6/12 combination types that individually represented >1% of the total MPT cohort. Breast cancer in combination with ovarian, thyroid, lymphoid hematological, or kidney cancer was overrepresented in the MPT cohort, whereas breast cancer in combination with non-melanoma skin was underrepresented.
Information regarding previous genetic testing was available for 405/440 (92%) probands. No molecular investigations had been performed in 91 (20.7%). 159 (36.1%) had undergone BRCA1 and BRCA2 testing, 87 (19.8%) had been assessed for Lynch syndrome (where microsatellite instability [MSI] and/or immunohistochemistry [IHC] analysis is considered an assessment), and 159 (20.7%) had had another germline genetic test. The mean number of genes analyzed (where MSI or IHC is considered an analysis of four Lynch syndrome genes) was four. Samples from 79 (18%) probands had undergone sequencing with a multi-gene panel assay, and the mean number of genes analyzed with these assays was 13.8.