Supplementary table 1.Previously reported renal carcinomas showing negative staining for SDHB or arising in individuals carrying germline SDH-x mutations. Case No. Study Age/Sex Family history of RCC germline SDH-x mutation / variation SDHB IHC Personal or family history of PCC/ PGL Other pathologies Follow up 1-2 Ricketts et al J Urol [22] 36/M Brother 25yrs Paternal uncle SDHB exon 1 deletion NA None NA DOD both siblings had a systematic presentation and suffered bone metastasis 3 Ricketts et al J Urol [22] 27/F Paternal grandmother SDHB exon 1 deletion NA None NA Disease free (17 mo) 4 Ricketts et al J Urol [22] 42/F None SDHB exon 1 deletion NA Sister carrier of the familial mutation NA Disease free (3.3 mo) 5 Ricketts et al J Urol [22] 32/F None SDHB c.137G>A NA Paternal aunt carrier of the familial mutation NA DOD (6.1 mo) Bone metastasis 6 Ricketts et al J Urol [22] 61/M None SDHB: c.268C>T NA Son (not screened for the familial mutation) NA Disease free (50.4mo) 7 Ricketts et al J Urol [22] 37/M NA SDHB c.286+2T>A NA NA NA Disease free (30 mo) 8 Ricketts et al J Urol [22] 28/M None SDHB c.379A>C NA None NA Disease free (36.2 mo) 9 Ricketts et al J Urol [22] 19/F None SDHB c.541-2A>G NA Mother (not screened for the familial mutation) NA Disease free (40.6 mo) 10-11 Ricketts et al J Urol [22] 17, 34*/F Mother RCC at the age of 55/ carrying SDHB c.286G>A NA None NA Disease free (212.4 mo) Mother AWD (65.8 mo) liver and bone metastasis
the familial mutation Female sibling of the maternal grandfather not screened for the familial mutation 12 Ricketts et al J Urol [22] 15/M None SDHB c.268C>T NA Paternal m cousins (siblings) Paternal distant f relative all carrying the familial mutation NA Disease free (10.8 mo) 13 Ricketts et al J Urol [22] 17/M None SDHB c.137G>A NA None NA Disease free (6.0 mo) 14 & Ojha Head Neck Pathol [23] Ricketts et al J Urol [22] 52/F Paternal Uncle 60yrs Maternal grandfather RCC in later years Mother’s sibling SDHB c.689G>A NA Daughter - pheochromocytoma age 20 Paternal Cousin 53 yrs - head and neck PGLs & one PGL - subsequently demonstrated to carry the familial mutation Multiple uterine fibroids Multiple benign & malignant neoplasms existed in the family: Maternal niece adrenal ganglioneuroma at the age of 13 Maternal aunt lung and brain malignancies at the age of 30 Mother’s sibling RCC, lung and breast carcinoma Disease free (35.5 mo)
15 Solis et al Clin Genet [24] 42/F No SDHB exon 1 deletion ND Positive personal history: Head and Neck PGL (carotid body) diagnosed at the age of 39 11 relatives out of 41 mutation carriers in this large family -8 extra-adrenal PGLs -3 PCCs Brother 36 yrs - papillary thyroid cancer Cousin 59 yrs -papillary bladder cancer Mother’s sibling 62 yrs -uterine adenocarcinoma Maternal aunt 72 yrs -lung cancer Benign disease course? 16 et al Fam Cancer [25] 65/F No SDHB c.600G>T ND Grandson - demonstrated to carry the familial mutation 17-18 Fairchild et al JAMA [26] Schimke et al Am J Med Genet A [27] 60/M maternal cousin F 26yrs SDHB c.418G>T ND Positive personal history: PGL 52 yrs 3 maternal cousins (Siblings: f 16 f 55 m 49) extra-adrenal PGLs Cousin left para-aortal neuroblastoma (9 mo), extra-adrenal PGL (16 yrs) with liver metastases (21 yrs) and a multifocal RCC (26 yrs) DOD (metastatic RCC) Cousin DOD (multifocal RCC) 26yrs 19 Vanharanta et al Am J Hum Genet [28] Neumann et al JAMA [29] Charis Eng J Natl Cancer Inst [30] 28/M SDHB c.79C>T ND Mother 55yrs -malignant PGL of the heart - demonstrated to carry the familial mutation Extra-adrenal PGL (PGL of the heart) DOD (6 yrs) 20 Vanharanta et al Am J Hum Genet [28] 26/M Sister 24yrs SDHB c.713_716delTCTC ND Positive personal history: Alive after long follow-up
Neumann et al JAMA [29] Charis Eng J Natl Cancer Inst [30] Paraganglioma 34yrs - this diagnosis was sequential to the respective one of RCC Sister -paraganglioma, which along with both renal tumors displayed somatic loss of the remaining wild type allele 21 Vanharanta et al Am J Hum Genet [28] Neumann et al JAMA [29] Charis Eng J Natl Cancer Inst [30] 24/F Brother SDHB c.713_716delTCTC ND Positive personal history: Paraganglioma 16yrs Brother -paraganglioma, which did not show somatic loss of the remaining wild-type allele DOD (1y 4 months) 22 Srirangalingam et al Clin Endocrinol (Oxf) [31] Srirangalingam et al Endocr Relat Cancer [32] et al [33] 26/F SDHB c.141G>A ND Positive personal history:: Extra-adrenal PGL 10yrs Family History Negative AWD (24 mo) Metastatic disease -12 mo following surgical resection (pelvic and supraclavicular R lymph node mass) -15 mo following surgical resection (evidence of progression within the right supraclavicular lymph nodes, partial metastatic destruction of the right scapula and new splenic metastasis) partial response to the multi-ta rget tyrosine kinase inhibitor sunitinib 23-25 Ricketts et al J Natl Cancer Inst [34] 24/M Father 24yrs SDHB c.136C>T ND None …
Paternal Uncle 73yrs subsequently demonstrated to carry the familial mutation 26 Ricketts et al J Natl Cancer Inst [34] 30/F SDHB c.137G>A ND None … 27 Ricketts et al J Natl Cancer Inst [34] 38/M SDHB c.32G>A ND None … 28 Cascón et al J Med Genet [35] 17/F None SDHB exon 1 deletion ND Positive personal history: Extra-adrenal PGL None AWD (10 years) osseous metastatic disease 29 Cascón et al Genes Chromosomes Cancer [36] 26/M None SDHB Whole gene (Exons 1-8) deletion ND Positive personal history: Head and Neck PGL 18yrs Positive family history (pers. com. Dr M Robledo) 30 Fleming et al Histopathology [37] 28/F SDHB c.759_765 + 7del ND 31 Fleming et al Histopathology [37] 69/F SDHB c.320G>A ND 32 Jasperson et al Familial Cancer [38] 30/M None SDHB c.590C>G ND None Positive family history (pers. com. Dr K Jasperson) Disease free (? Mo)
33 Malinoc et al Endocr Relat Cancer [39] 68/ F No SDHC c.3G>A Neg/ Pos Positive personal history: Head and Neck PGL 42yrs Son Head and Neck PGL 34-36 Ricketts et al J Urol [22] 49/F 4 cousins (f siblings 44 52 53/68** and a male 46 yrs) Nephew 40 yrs carrier of the familial mutation SDHC c.397C>T ND Cousin (F) carrier of the familial mutation that did not develop RCC HN PGL (carotid PGL?) Disease free (240.8 mo) Cousin M DOD (133.5 mo) Cousin F Disease free (62.0 mo) Cousin F** AWD (54.8) Cousin F Dead of other cause (182.7 mo) Nephew Disease free (12.3 mo) 37 Ricketts et al J Urol [22] 45/ M None SDHD c.239G>T ND Positive personal history: PGL 17,21,28,31,45,45yrs Extensive family history of CBTs (paternal grandfather, father, paternal uncle and two aunts) Brother Pheo DOD (18.7 mo) (osseous, lung and retroperitoneal metastatic disease)
38 Ni et al Am J Hum Genet [40] 62/F No SDHD c.34G>A ND None Thyroid gland & breast: benign pathology Uterine leiomyomas 39 Ni et al Am J Hum Genet [40] 53/ F No SDHD c.433C>A ND None Breast carcinoma Thyroid gland: benign pathology 40 Gill et al N Engl J Med [12] Gill et al Am J Surg Pathol [4] 34/F Nephew carrying the familial mutation SDHB c.166-170 delCCTC Neg Nephew Extra-adrenal PGL (intra-abdominal) Sister 31 yrs Breast cancer subsequently demonstrated to carry the familial mutation Disease free (30 years) 41-42 Papathomas et al Eur J Endocrinol [41] 25/M 23/M Brother 23 yrs Brother 25 yrs SDHB c.3G>A Neg/Neg Neg Positive personal history: Extra-adrenal PGL (1st brother) Negative family history AWED/31 AWED/28 43 Papathomas et al Eur J Endocrinol [41] 36/M None SDHB exon 3 deletion Neg Positive personal history: HN PGLs (30/34 yrs) Negative family history AWD/47 (liver & splenic metastatic disease--- intraabdominal recurrent disease) 44 Paik et al. J Clin Oncol [16] 27/M Male second cousin Metastatic RCC (DOD 37 yrs) SDHB c.88delC Neg None Mother Asymptomatic carrier of the familial mutation DOD at age 29 yrs 2.5 years after widespread metastatic disease presentation (bone & liver metastatic disease) 45 Gill et al N Engl J Med [12] Gill et al 28/M Maternal Aunt subsequently demonstrated to carry the SDHB c.166-170 delCCTC Neg Positive personal history: Extra-adrenal PGL (intra-abdominal) Mother 31 yrs Breast cancer subsequently demonstrated to the familial mutation Disease free (4 years)
Am J Surg Pathol [4] familial mutation Synchronous tumors also showed negative staining for SDHB 46 Gill et al N Engl J Med [12] Gill et al Am J Surg Pathol [4] 21/F None SDHB c.268C>T Neg Mother 43,45 yrs -subsequently demonstrated to carry the familial mutation -metachronous tumors showed SDHB immunonegativity Multiple HN PGLs carotid body (R) PGL (43yrs); jugular (L) PGL and vagal (L) PGL (45 yrs) Disease free (7 years) 47 Gill et al N Engl J Med [12] Gill et al Am J Surg Pathol [4] 22/M None SDHB: c.423+1G>A Neg Nephew 19yrs subsequently demonstrated to carry the familial mutation Extra-adrenal PGL (intra-abdominal/ metastatic) Brother 44yrs -subsequently demonstrated to the familial mutation -synchronous tumors (PGL & GIST) also showed SDHB immunonegativity Brother 44yrs SDH deficient GIST DOD (1 year) progressive metastatic disease
Extra-adrenal PGL (intra-abdominal) 48 et al et al Histopathology [42] Gill et al Am J Surg Pathol [4] Fleming et al Histopathology [37] 58/F None SDHB c.72+1G>T Neg Daughter - previous diagnosis of a malignant Pheo accounting for genetic screening and subsequent detection of RCC in the mother - to carry the familial mutation concurrently with her mother Disease free 2 years 49 Gill et al Pathology [17] 22/F None SDHC c.380A>G Neg None Her sister/mother are asymptomatic carriers of the familial mutation Gastric GIST (+ metastasis) 12/ 33 yrs Papillary thyroid carcinoma 30 yrs Disease free (? Mo) 50 Miettinen et al AIMM[43] 40/M None Not performed (SDHB negative by IHC) Neg None Adrenal Metastasis