Table 21.2.

Summary of CFS-associated genes and their implications in human diseases

Fragile site	Induction method	Cyto-band	Freq. in APH (%)^a	Assoc. genes	Disease
FRA1A	APH	1p36	0.488
FRA1B*	APH	1p32	1.491	DAB1	Brain and endometrial cancer (McAvoy et al. 2008)
FRA1C	APH	1p31.2		IL23R-C1orf141	Vogt-Koyanagi-Harada syndrome; LOH/MSI associated with advanced tumor stage in prostate cancer (Brys et al. 2013; Hou et al. 2014)
FRA1D	APH	1p22	0.009
FRA1E*	APH	1p21.2	0.067	DPYD	Colorectal, breast, and ovarian cancer (Hormozian et al. 2007)
FRA1F	APH	1q21	0.098
FRA1G	APH	1q25	0.799
FRA1I	APH	1q44	2.299		Nasopharyngeal carcinoma (Xia et al. 1988)
FRA1K	APH	1q31	0.138
FRA1L	APH	1p31	0.479
FRA2C*	APH	2p24.2 2q24.3	1.513	MYCN	Two FSs, FRA2Ccen and FRA2Ctel, flank the MYCN amplicon; locus-specific and genomic rearrangements in neuroblastoma and multiple cancers (Blumrich et al. 2011; Lipska et al. 2013)
FRA2D	APH	2p16.2	2.325
FRA2E	APH	2p13	0.235		Posttransplant diffuse large B-cell lymphoma (Rinaldi et al. 2010)
FRA2F	APH	2q21.3	0.994	LRP1B	Alzheimer’s; Kawasaki disease (Lin et al. 2014; Shang et al. 2015)
FRA2G*	APH	2q31	0.306	GAD1	Schizophrenia (Bharadwaj et al. 2013)
FRA2H*	APH	2q32.1	3.905	DIRC1, PMS1, MIRN589, MIRN1245	Breakpoints characterized in K562 cells (Pelliccia et al. 2010)
FRA2I	APH	2q33	1.722
FRA2J	APH	2q37.3	0.657
FRA3A	APH	3p24.2	1.327
FRA3B*	APH	3p14.2	14.153	FHIT	Loss or change of FHIT expression associated with common cancers including bladder, esophageal, lung, breast, and prostate cancers (Saldivar et al. 2010)
FRA3C	APH	3q27	1.061
FRA3D	APH	3q25	0.546		FS expression linked to schizophrenia (Demirhan et al. 2006)
FRA4A	APH	4p16.1	0.612
FRA4C	APH	4q31.1	2.175
FRA4D	APH	4p15	0.111
FRA4F*	APH	4q22	0.683	GRID2	Autosomal recessive cerebellar ataxia associated with retinal dystrophy; ataxia and tonic upgaze (Hills et al. 2013; Van Schil et al. 2015)
FRA5C	APH	5q31.1	0.373	SMAD5	Copy number gain and increased expression in human hepatocellular carcinoma cells (Zimonjic et al. 2003)
FRA5D	APH	5q15	0.834		Concomitant t(5;21)(q15;q22) and del(5)(q13q33) events in myelodysplastic syndrome (Kasi Loknath Kumar et al. 2016)
FRA5E	APH	5p14	0.293		Copy number loss observed at 52.4% in early Barrett’s esophagus (Lai et al. 2010)
FRA5F	APH	5q21	0.515		FS expression significantly higher in patients with rectum cancer and their first-degree relatives (Tunca et al. 2000)
FRA6B	APH	6p25.1	0.985		Copy number change associated with osteoporotic fractures, gyral pattern anomaly, and speech and language disorder in two dizygotic twins (Bozza et al. 2013; Oei et al. 2014)
FRA6C	APH	6p22.2	0.062	BAC CITB.564_C_7	High LOH in cervical tumors; HPV integration site in cervical tumor CC171 (Rader et al. 1996; Thorland et al. 2000)
FRA6E*	APH	6q26	2.823	PARK2	Parkinson’s; poor outcome in breast cancer (Ambroziak et al. 2015; Letessier et al. 2007)
FRA6F*	APH	6q21	0.608	REV3L, DIF13, FKHRL, etc.	Cancer; schizophrenia (Karayianni et al. 1999; Morelli et al. 2002)
FRA6G	APH	6q15	0.115		Chromosome breakpoints in metastatic melanoma (Limon et al. 1988)
FRA7B*	APH	7p22	0.799	THSD7A, SDK1, MAD1L1, MIRN589, MIRN339	Recurrent breakpoint in multiple cancers (Bosco et al. 2010)
FRA7C	APH	7p14.2	0.541
FRA7D	APH	7p13	0.55		Highly expressed in a female presenting severe immunodeficiency (Conley et al. 1986)
FRA7E*	APH	7q21.2	0.501
FRA7F	APH	7q22	0.107		Fragile site expression linked to bipolar disorder and schizophrenia (Demirhan et al. 2006, 2009)
FRA7G*	APH	7q31.2	0.111	Caveolin-1, caveolin-2, TESTIN	Reduced TESTIN expression in 22% of cancer cell lines and 44% of the cell lines derived from hematological malignancies; caveolin-1 gene proposed to be a candidate tumor suppressor (Engelman et al. 1998; Tatarelli et al. 2000)
FRA7H*	APH	7q32.3	2.374		Translocation involving 7q32 found in the RC-K8 cell line derived from a patient with terminal diffuse large B-cell lymphoma (Mishmar et al. 1998; Schneider et al. 2008)
FRA7I*	APH	7q36	0.084	CNTNAP2	Implicated in ASD (Rodenas-Cuadrado et al. 2014)
FRA7J	APH	7q11	0.83	LIMK1, EIF4H(WBSCR1)	Breakpoint found between the LIMK1 and EIF4H (WBSCR1) genes in patients with Williams-Beuren syndrome and ASD (Plaja et al. 2015)
FRA8B	APH	8q22.1	0.923
FRA8C*	APH	8q24.1	0.799	MYC	Cluster of HPV18 integrations at 8q24 in primary cervical carcinoma; CFS expression frequent in bladder cancer (Ferber et al. 2004; Moriarty and Webster 2003)
FRA8D	APH	8q24.3	0.182
FRA9D	APH	9q22.1	0.231		FS expression frequent in bladder cancer (Moriarty and Webster 2003)
FRA9E*	APH	9q32		PAPPA	LOH, particularly loss of PAPPA, is linked to ovarian cancer (Callahan et al. 2003)
FRA10D	APH	10q22.1	0.306	CTNNA3	Decreased gene expression of CTNNA3 in oropharyngeal squamous cell carcinomas (Gao et al. 2014)
FRA10E	APH	10q25.2	0.191
FRA10F*	APH	10q26.1	0.408	FATS
FRA10G*	APH	10q11.2	0.142	RET, NCOA4	FS generates oncogenic RET/PTC rearrangements in human thyroid cells (Gandhi et al. 2010)
FRA11C	APH	11p15.1	0.51		FS expression frequent in bladder cancer (Moriarty and Webster 2003)
FRA11D	APH	11p14.2	0.928
FRA11E	APH	11p13	0.621		Translocation breakpoints at 11p13 found in CML patients.
FRA11F	APH	11q14.2	1.771		Gene amplification linked to FRA11F expression in oral cancer (Reshmi et al. 2007)
FRA11G*	APH	11q23.3	0.098		Interstitial deletions at 11q23.3 associated with abnormal ultrasound findings during prenatal diagnosis (Fechter et al. 2007; Liu et al. 2014)
FRA11H*	APH	11q13	0.075
FRA12B	APH	12q21.3	0.364
FRA12E	APH	12q24	0.288
FRA13A*	APH	13q13.2	1.061	NBEA	Neuropsychiatric disorders (Savelyeva et al. 2006a, b)
FRA13C	APH	13q21.2	0.124		HPV16 integration site in the cervical tumor cell line SiHa (Thorland et al. 2000)
FRA13D	APH	13q32	0.178		Fragile site expression linked to bipolar disorder and schizophrenia (Demirhan et al. 2006, 2009)
FRA14B	APH	14q23	1.429		Found as a constant FS in bloom syndrome cell lines (Barbi et al. 1984; Shiraishi and Li 1993)
FRA14C	APH	14q24.1	0.382		Found as frequent HPV integration site in HPV-related cancers (Bodelon et al. 2016)
FRA15A	APH	15q22	0.08	RORA	RORA gene expression is low in breast, prostate, and ovarian cancers (Zhu et al. 2006)
FRA16C	APH	16q22.1	0.488		High expression at FRA16B/C found in peripheral blood lymphocytes in the male of a couple having trouble conceiving. Chr 16 instability detected in the sperm of the male and in embryos (Martorell et al. 2014)
FRA16D*	APH	16q23.2	7.576	WWOX/WOX1/FOR	WWOX gene dysregulation associated with multiple cancers, including pancreatic adenocarcinoma, renal cell carcinoma, and endocrine and exocrine carcinomas (Li et al. 2014)
FRA17B	APH	17q23.1	0.071		HPV integration site in cervical tumor CC226 (Thorland et al. 2000)
FRA18A	APH	18q12.2	0.475		High frequency of LOH on chr 18 in esophageal squamous cell carcinoma (Karkera et al. 2000)
FRA18B	APH	18q21.3	0.182	DCC	Found as FSs with frequent interstitial deletions in HIV lymphomas (Capello et al. 2010)
FRA18C*	APH	18q22.1–18q22.2	0.067	DOK6	FS expression in the father of a patient with Beckwith-Wiedemann syndrome and a chromosome truncation 18q22-qter (Debacker et al. 2007)
FRA20B	APH	20p12.2
FRA22B	APH	22q12.2	0.275		Elevated FS expression in bone marrow and peripheral blood of young cigarette smokers (Kao-Shan et al. 1987)
FRAXB*	APH	Xp22.31	5.494	STS, GS1 HDHD1 MIR4767	Deletions within FRAXB seen in 15% of primary tumors and cell lines examined (Arlt et al. 2002)
FRAXC	APH	Xq22.1	2.121	DMD, IL1RAPL1
FRAXD	APH	Xq27.2	0.209
FRA1H*	5-AZ	1q41–q42.1	0.129	USH2A, ESRRG, MIRN194–1, MIRN215
FRA1J	5-AZ	1q12	0.12
FRA9F	5-AZ	9q12	0.453
FRA19A	5-AZ	19q13	0.053
FRA4B	BrdU	4q12	0.142
FRA5A	BrdU	5p13	0.191
FRA5B	BrdU	5q15
FRA6D	BrdU	6q13	0.031
FRA9C	BrdU	9p21
FRA10C	BrdU	10q21	0.089
FRA13B	BrdU	13q21
FRA4E	UC	4q27	0.382

Molecularly mapped fragile sites are indicated by an asterisk

5-AZ, 5-azacytidine, APH aphidicolin, BrdU bromodeoxyuridine, UC unclassified, FS fragile site, LOH loss of heterozygosity, MSI microsatellite instability, ASD autism spectrum disorder

Data derived from Mrasek et al. (2010)