Table 3. Standardised incidence ratios of cancer in a nationwide cohort of patients with mitochondrial dysfunction, overall and according to proband status, subgroup of mitochondrial mutation, sex and current age.

Mitochondrial mutation	Cohort members	obs	exp	SIR	95% CIa
Main cohort (all mutations)	311	19	18.0	1.06	0.68 to 1.63
All genetically certain casesb	162	10	9.51	1.05	0.60 to 1.85
Stratification by proband status
Probands	61	0	1.76	—	—
Non-probands	250	19	16.2	1.17	0.76 to 1.81
Stratification by mutational subgroup
Maternally inherited mDNA mutation	278	19	17.4	1.09	0.71 to 1.69
Register based	134	8c	6.52	1.23	0.70 to 2.17
Clinic based	144	11	10.9	1.01	0.58 to 1.76
m.3243A>G mutation	218	13	13.8	0.94	0.53 to 1.67
Non-m.3243A>G mutationd	60	6c	3.61	1.66	0.98 to 2.83
Other mutations	33	0	0.60	—	—
De novo mDNA mutation	8	0	0.13	—	—
Nuclear DNA mutation	25	0	0.47	—	—
Stratification by sex and current age
Female	174	15	14.0	1.07	0.66 to 1.74
Male	137	4c	4.03	0.99	0.39 to 2.51
Current age<50	282e	5c	5.72	0.87	0.38 to 1.98
Current age≥50	103e	14	12.3	1.14	0.72 to 1.80

Abbreviations: CI=confidence interval; exp=expected number of primary cancers during follow-up; mDNA=mitochondrial DNA; nDNA=nuclear DNA; obs=observed number of primary cancers during follow-up; SIR=standardised incidence ratio.

^aP-homogeneity: proband vs non-proband (P-value not evaluated), maternally inherited mDNA mutation vs other mutations (P-value not evaluated), female vs male= 0.88 and current age less than 50 vs current age 50 or older =0.52, register-based vs clinic-based=0.60 and m.3243A>G vs non-m.3243A>G =0.19.

^bGenetically, certain cases denotes cohort members with a genetically confirmed diagnosis, that is, in this subanalysis, the following cohort members were excluded: (i) cohort members identified only through the Danish Family Relations Database, (ii) 12 tested cohort members from families with the m.3243A>G-mutation in whom the degree of mDNA heteroplasmy was very low, that is, below the detection limit of the assay of 1% and (iii) 3 tested cohort members from a family where the m.8344A>G mutation was detected in the proband but neither in the mother nor in the tested siblings. This proband was diagnosed at the beginning of the study period, where the assay (direct sequencing) had an estimated sensitivity of approximately 15%, that is, a low level of heteroplasmy for the tested relatives cannot be ruled out.

^cAs asymptotic and exact confidence intervals may differ when having few cancer cases, we also estimated exact confidence intervals for mutation groups with less than 10 cancer cases: register-based (0.53 to 2.42), non-m.3243A>G mutation (0.61 to 3.61), male (0.27 to 2.54) and current age<50 (0.28 to 2.04). Use of exact confidence intervals did not change the study conclusions.

^dThe non-m.3243A>G-group (register-based and clinic-based cohort members) consisted of the following mutations (cohort members eligible for follow-up, obs/exp): m.8344A>G (31, 4/1.99), m.4078A>G (9, 0/0.07), m.9176T>C (5, 0/0.35), m.8993T>C (15, 2/1.20).

^eAs current age is a time-dependent variable, the same cohort member can contribute to both categories as exposed and explaining why the number of cohort members in the two categories exceeds 311.